Benzylated PDE4 inhibitors

ABSTRACT

The present invention is directed to a method for reducing the emetogenic effects of PDE inhibitors, and more particularly is directed to compounds having PDE4 inhibition activity with little or no emetogenic side-effects, and chemical methods including benzylation for preparing such compounds. A benzyl group may be attached to either a carbon or nitrogen atom of a PDE4 inhibitor. Suitable benzylation chemistry is to extract a hydrogen from a PDE4 inhibitor, preferably with a base, and then react the resulting nucleophilic PDE4 inhibitor with a benzylating agent, e.g., benzyl bromide or a derivative thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.09/810,085, filed Mar. 16, 2001 now U.S. Pat. No. 6,555,572, nowallowed, and claims the benefit of U.S. Provisional Patent ApplicationNo. 60/190,337 filed Mar. 16, 2000, where these applications areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention is directed to a method for reducing theemetogenic effects of PDE inhibitors, and more particularly is directedto compounds having PDE4 inhibition activity with little or noemetogenic side-effects, and chemical methods including benzylation forpreparing such compounds.

BACKGROUND OF THE INVENTION

Enzymes known as phosphodiesterases (PDEs) function in vivo tohydrolytically cleave the 3′-phosphodiester bond of cyclic nucleotidesto thereby form the corresponding 5′-monophosphate. For instance,certain PDEs can hydroylze the 3′-phosphodiester bond of adenosine3′,5′-cyclic monophosphate (cAMP) so as to form 5′-adenosinemonophosphate (5′-AMP), and/or can hydrolyze the 3′-phosphodiester bondof guanosine 3′,5′-cyclic monophosphate (cGMP) so as to form5′-guanosine monophosphate (5′-GMP). These cyclic nucleotides exert asignificant impact on cellular processes by, for example, convertinginactive protein kinase enzymes into an active form. The active form ofthe protein kinase catalyzes various phosphorylation processes thatimpact on fundamental cellular processes including transcriptionalregulation, ion channel function, and signaling protein activity.

Researchers investigating PDEs generally agree that there are at leasteleven distinct PDE families, differentiated on the basis of amino acidsequence, substrate specificity and sensitivity to endogenous andexogenous regulators. These families are commonly known as PDE1 throughPDE11. In addition, researchers found that cyclic nucleotideconcentration is a significant factor in the course of the in vivoinflammatory response. Accordingly, much research has been directed tomethods for influencing the concentration of cyclic nucleotides as ameans to influence the inflammatory response, and particular attentionhas been directed at PDE4 activity. One promising area of research isthe development of small organic molecules that inhibit PDE activity. Byinhibiting PDE activity, these small molecules reduce the amount ofcyclic nucleotide that is converted into the (inactive) corresponding5′-monophosphate, thereby elevating cyclic nucleotide concentration, andindirectly increasing protein kinase activity within the cell.

Many major pharmaceutical companies are working to develop specificsmall organic molecules into pharmaceutical compositions that functionas PDE inhibitors. ROLIPRAM™ (Schering AG) is an example of an earlyattempt to develop such a composition directed to PDE4. However, whileROLIPRAM™ exhibited marked anti-inflammatory activity, it was also foundto demonstrate unwanted side effects including emesis (also known asnausea and vomiting) and potentiation of gastric acid secretion. Theseundesired side effects caused ROLIPRAM™ to be withdrawn from developmentas an anti-inflammatory pharmaceutical. An understanding of the cause ofthese side-effects, and approaches to mitigate them, subsequently becametopics of intense study.

It is now recognized that PDE4 exists in two distinct forms, i.e., twoconformers. One conformer, known variously as HPDE4 or HARB, isparticularly prevalent in the gastrointestinal tract and central nervoussystem, has a high affinity for ROLIPRAM™ (i.e., has a High AffinityROLIPRAM™ Binding Site, “HARBS”), and is considered responsible for theunwanted side-effects. The other conformer is known variously as LPDE4or LARB, is found in immunocompetent cells, and has a low affinity forROLIPRAM™. Researchers are seeking to develop small molecules thatinhibit the catalytic activity of LPDE4 rather than bind to HPDE4, i.e.,molecules that have a low LPDE4:HPDE4 ratio where the numerator anddenominator are the appropriate IC₅₀ values. In other words, researchersare seeking so-called “second generation” inhibitor molecules thatinteract with the LPDE4 catalytic site of PDE4, rather than the HPDE4ROLIPRAM™ binding site, to provide desirable anti-inflammatory effectwithout unwanted side-effects such as emesis.

The present invention is directed to fulfilling this need in the art,and providing further related advantages as set forth more completelyherein.

For additional and more detailed discussion of PDE enzymes, includingthe history of their discovery, their characterization andclassification, their in vivo activity, their inhibition by smallorganic molecules, and current clinical efforts directed to providingpharmaceutical compositions containing these small molecules, see, e.g.,Burnouf, C. et al. “Phosphodiesterase 4 Inhibitors” Annual Reports inMedicinal Chemistry, Vol. 33, Chap. 10, pp 91-109, 1998 (Bristol, J. A.,ed.); Essayan, D. M. “Cyclic Nucleotide Phosphodiesterase (PDE)Inhibitors and Immunomodulation” Biochemical Pharmacology 57:965-973,1999; Souness, J. E. and Foster, M. “Potential of phospodiesterase typeIV inhibitors in the treatment of rheumatoid arthritis” Idrugs1(5):541-553, 1998; Souness, J. E. et al. “Immunosuppressive andanti-inflammatory effect of cAMP phosphodiesterase (PDE) type 4inhibitors” Immunopharmacology 47: 127-162, 2000; and Torphy, T. J.“Phosphodiesterase Isozymes” Am J. Respir. Crit. Care Med. 157:351-370,1998, as well as the numerous references cited in these articles.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method for improving thetherapeutic ratio of PDE4 inhibitors through reduction or elimination ofemetogenic properties while allowing retention of PDE activity. In oneaspect, the method comprises benzylation of a PDE4 inhibitor, whereinthe benzylation places a benzyl group on a carbon atom of a PDE4inhibitor, to provide a benzylated PDE4 inhibitor. In one aspect, thePDE4 inhibitor is ROLIPRAM™, while in another aspect the PDE4 inhibitoris ARIFLO™. The benzylation may replace an extractable hydrogen of thePDE4 inhibitor with a benzyl group. For instance, the PDE4 inhibitor maybe reacted with a base in order to extract the extractable hydrogen,followed by reaction with a benzylating agent. In one aspect, the PDE4inhibitor has a carbonyl group and the extractable hydrogen is locatedalpha to (i.e., next to) the carbonyl group. In another aspect, the PDE4inhibitor has a carbonyl group and benzyl group is located beta to(i.e., with one intervening atom between) the carbonyl group. In anotheraspect, the PDE4 inhibitor has a carbonyl group and benzyl group islocated gamma to (i.e., with two intervening atoms between) the carbonylgroup. The extractable hydrogen may be removed under chemical conditionsand replaced with a benzyl group.

In one aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 4carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², and OR² wherein and R² at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, phenyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the phenyl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat either (a) at least one R¹ is OR², or (b) the benzyl ring containsat least two R¹ groups that are not hydrogen.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 is carbon;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat R₁ is hydrogen at either 1, 2, or 3 occurrences of n, but not 4 or5 occurrences.

In one aspect of the present invention, the benzylated PDE4 inhibitorcomprises a benzyl group, and independently of the benzyl group thebenzylated PDE4 inhibitor further comprises a phenyl group of theformula

wherein p is 5; and R³ at each occurrence is independently selected fromhalogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In one aspect ofthe invention R³ is OR⁴ in at least one occurrence wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl.

In one aspect of the present invention, the phenyl group has the formula

wherein R⁷ is selected from methyl, ethyl, difluoromethyl andtrifluoromethyl; and R⁸ is selected from C₃-C₈alkyl, alkoxyalkyl having3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, phenylalkyl having 1-8 carbons in the alkylportion, phenylaminoalkyl having 2-6 carbons in the alkyl portion andthe amino may be optionally substituted with C₁-C₄alkyl and indanyl;wherein the alkyl portion of an R² group may be optionally substitutedwith one or more fluorine atoms, hydroxyl or C₁-C₄alkoxy; and the arylportion (e.g., phenyl) of an R² group may be optionally substituted withC₁-C₄alkyl, C₁-C₄alkoxy or halogen. Optionally, R⁸ is not cyclopentyl.

Thus, in one aspect, the present invention provides a method forimproving the therapeutic ratio of PDE4 inhibitors through reduction orelimination of emetogenic properties while allowing retention of PDEactivity, the method comprising benzylation of a PDE4 inhibitor, whereinthe benzylation places a benzyl group on a carbon atom of a PDE4inhibitor, to provide a benzylated PDE4 inhibitor.

In one aspect, the PDE4 inhibitor is ROLIPRAM™ or an analog thereof. Forinstance, the C-benzylated ROLIPRAM™ or analog thereof may have theformula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; A is selected from a direct bond, optionally substitutedC₁-C₅alkylene, optionally substituted C₂-C₅alkenyl and optionallysubstituted phenylene; p is 5; and R³ at each occurrence isindependently selected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴wherein q=0, 1, 2, or 3 and R⁴ at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl,heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R⁴ group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the aryl portion of anR⁴ group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy orhalogen. Optionally, A is a direct bond; and in at least one occurrence,R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl.

For instance, the benzylated ROLIPRAM™ or analog thereof may have theformula:

In another aspect the PDE4 inhibitor is ARIFLO™ or an analog thereof.For instance, the C-benzylated ARIFLO™ or analog thereof may have theformula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; R⁵ isselected from H, halogen, cyano, C₁-C₈alkyl, and C₁-C₈alkoxy; and R⁶ isselected from H, positively charged species, and C₁-C₈alkyl. Optionally,in at least one occurrence, R³ is OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl; and R⁶ is selectedfrom H and positively charged species. For instance, the benzylatedARIFLO™ or analog thereof may have the formula

As another example, the benzylated ARIFLO™ or analog thereof may havethe formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; R⁵ isselected from H, halogen, cyano, C₁-C₈alkyl, and C₁-C₈alkoxy; and R⁶ isselected from H, positively charged species, and C₁-C₈alkyl. Optionally,in at least one occurrence, R³ is OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl; and R⁶ is selectedfrom H and positively charged species. For instance, the benzylatedARIFLO™ or analog thereof may have the formula

In another aspect, the present invention provides a method for improvingthe therapeutic ratio of PDE4 inhibitors through reduction orelimination of emetogenic properties while allowing retention of PDEactivity, where the method comprises benzylation of a PDE4 inhibitor,wherein the benzylation places a benzyl group (Bzl) on a nitrogen atomof a PDE4 inhibitor, to provide an N-benzylated PDE4 inhibitor, whereinthe N-benzylated PDE4 inhibitor comprises at least one benzyl group(Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In one embodiment, either (a) at least one R¹ is OR², or (b) the benzylring contains at least two R¹ groups that are not hydrogen. In anotherembodiment, each of the numerals 1, 2, 3, 4 and 5 is carbon. In anotherembodiment, n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R² group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the phenyl portion ofan R² group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxyor halogen. In a preferred embodiment, each of the numerals 1, 2, 3, 4and 5 may be carbon or nitrogen, with the proviso that the ring isaromatic and contains at least 3 carbon atoms; n is 5 and R¹ at eachoccurrence is independently selected from halogen and OR² wherein R² ateach occurrence is independently selected from H and C₁-C₈alkyl; withthe provisos that the benzyl ring contain no more than three hydrogensubstituents and no more than one methoxy substituent.

The N-benzylation method may be applied to a PDE4 inhibitor containing anitrogen atom, preferably an amide group where the nitrogen atom of theamide group undergoes a benzylation reaction to place a benzyl group onthat nitrogen atom. Suitable PDE4 inhibitors for the N-benzylationreaction of the present invention include, without limitation,ROLIPRAM™, WAY-PDA-641, Ro-20-1724, RP 73401, CP-80,633-A, AROFYLLINE™and CIPAMFYLLINE™. The benzylation may replace an extractable hydrogenof the PDE4 inhibitor with a benzyl group. For instance, the PDE4inhibitor may be reacted with a base in order to extract the extractablehydrogen, followed by reaction with a benzylating agent. In one aspect,the PDE4 inhibitor has an amide group and the extractable hydrogen islocated on the nitrogen atom of the amide group.

In one aspect, the N-benzylated ROLIPRAM™ or analog thereof prepared bythe benzylation method of the present invention has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; A is selected from a direct bond, optionally substitutedC₁-C₅alkylene, optionally substituted C₂-C₅alkenyl and optionallysubstituted phenylene; p is 5 and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.Optionally, A is a direct bond; p is 1, 2, or 3; and in at least oneoccurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. For instance, the benzylatedROLIPRAM™ or analog thereof may have the formula

In another aspect of the inventive method for N-benzylation, the PDE4inhibitor is WAY-PDA-641 or an analog thereof. For instance, thebenzylated WAY-PDA-641 or analog thereof may have the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Forinstance, the benzylated WAY-PDA-641 or analog thereof may have theformula:

In another aspect of the inventive method for N-benzylation of a PDE4inhibitor, the PDE4 inhibitor is Ro-20-1724 or an analog thereof. In oneaspect, the benzylated Ro-20-1724 or analog thereof may have theformula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Forinstance, the N-benzylated Ro-20-1724 or analog thereof may have theformula:

In another aspect, the N-benzylated Ro-20-1724 or analog thereof has theformula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Forinstance, the benzylated Ro-20-1724 or analog thereof may have theformula:

In another aspect, the N-benzylation reaction of the present inventionemploys RP 73401 or an analog thereof as the PDE4 inhibitor. Forexample, the benzylated RP 73401 or analog thereof may have the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Forinstance, the benzylated RP 73401 or analog thereof may have theformula:

In another aspect of the inventive method for N-benzylation of a PDE4inhibitor, the PDE4 inhibitor is CP-80,633-A or an analog thereof. Forexample, the benzylated CP-80,633-A or analog thereof may have theformula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Forinstance, the benzylated CP-80,633-A or analog thereof may have theformula:

In another aspect of the inventive method for N-benzylation of a PDE4inhibitor, the PDE4 inhibitor is AROFYLLINE™ or an analog thereof. Forexample, the benzylated AROFYLLINE™ or analog thereof may have theformulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5 and R³ at each occurrence is independently selectedfrom halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, p is 1,2 or 3; and in at least one occurrence, R³ is halogen or OR⁴ wherein R⁴is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl.For example, the benzylated AROFYLLINE™ or analog thereof may have theformula

As another example the benzylated AROFYLLINE™ or analog thereof may havethe formula

More specific examples of benzylated AROFYLLINE™ or analog thereofcompounds prepared by the present invention have the formula:

As another specific example the benzylated AROFYLLINE™ or analog thereofmay have the formula:

In another aspect of the inventive method for N-benzylation of a PDE4inhibitor, the PDE4 inhibitor is CIPAMFYLLINE™ or an analog thereof. Forexample, the benzylated CIPAMFYLLINE™ or analog thereof may have theformulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group.

In addition the above methods for improving the therapeutic ratio ofPDE4 inhibitors through reduction or elimination of emetogenicproperties while allowing retention of PDE activity, the presentinvention provides PDE4 inhibitors having benzyl groups.

In one aspect, the present invention provides a C-benzylated ROLIPRAM™or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; A is selected froma direct bond, optionally substituted C₁-C₅alkylene, optionallysubstituted C₂-C₅alkenyl and optionally substituted phenylene; p is 5and R³ at each occurrence is independently selected from halogen, nitro,R⁴, NR⁴ _((q)), and OR wherein q=0, 1, 2, or 3 and R⁴ at each occurrenceis independently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, A isselected from a direct bond, C₁-C₅alkylene, C₂-C₅alkenyl and phenylene.Optionally, A is a direct bond; and in at least one occurrence, R³ isOR⁴ wherein R² is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In a preferred embodiment, R³ at the para positionrelative to A is alkoxy, and R³ at one meta position is selected fromalkyl having at least 3 carbons and alkoxy having at least 3 carbons.

For example, the present invention provides a compound having theformula

In another aspect the present invention provides an N-benzylatedROLIPRAM™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; A is selected froma direct bond, optionally substituted C₁-C₅alkylene, optionallysubstituted C₂-C₅alkenyl and optionally substituted phenylene; p is 5and R³ at each occurrence is independently selected from halogen, nitro,R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, A is adirect bond; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Inanother optional embodiment at least one R¹ is OR². In a preferredembodiment, at the meta position relative to the A group on theR³-substituted phenyl ring, R³ is alkoxy having at least three carbonatoms, excluding cyclopentyloxy, and at the para position R¹ is nothydrogen. In one embodiment, A is selected from a direct bond,C₁-C₅alkylene, C₂-C₅alkenyl and phenylene.

In another aspect the present invention provides an N-benzylatedROLIPRAM™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen and OR² wherein R² at each occurrence is independentlyselected from H and C₁-C₈alkyl; with the provisos that the benzyl ringcontain no more than three hydrogen substituents and no more than onemethoxy substituent; A is selected from a direct bond, optionallysubstituted C1-C5alkylene, optionally substituted C²-C⁵alkenyl andoptionally substituted phenylene; p is 5 and R³ at each occurrence isindependently selected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴wherein q=0, 1, 2, or 3 and R⁴ at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl,heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R⁴ group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the aryl portion of anR⁴ group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy orhalogen. Optionally, A is a direct bond; and in at least one occurrence,R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In another optional embodiment at least one R¹ isOR². In a preferred embodiment, at the meta position relative to the Agroup on the R³-substituted phenyl ring, R³ is alkoxy having at leastthree carbon atoms, excluding cyclopentyloxy, and at the para positionR¹ is not hydrogen. In one embodiment, A is selected from a direct bond,C₁-C₅alkylene, C₂-C₅alkenyl and phenylene.

For instance, the present invention provides a compound having theformula

In another aspect the present invention provides a benzylated ARIFLO™ oranalog thereof compound of the formulae

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴, NR⁴_((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; R⁵ is selected fromH, halogen, cyano, C₁-C₈alkyl, and C₁-C₈alkoxy; and R⁶ is selected fromH, positively charged species, and C₁-C₈alkyl. Optionally, in at leastone occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl; and R⁶ is selected from H andpositively charged species.

For instance, the present invention provides compounds having theformulae

In another aspect the present invention provides a benzylatedWAY-PDA-641 or analog thereof compound of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴; NR⁴_((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, in atleast one occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. For instance, the presentinvention provides compound having the formula:

In another aspect the present invention provides a benzylated Ro-20-1724or analog thereof compound of the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴, NR⁴_((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, in atleast one occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl. In a preferred embodiment,relative to the methylene bridge to the heterocyclic ring, R³ at thepara position is alkoxy, and R³ at a meta position is alkoxy having atleast three carbon atoms. For example, the present invention provides acompound having the formulae

In another aspect the present invention provides a benzylated RP 73401or analog thereof compound of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴, NR⁴_((m)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, in atleast one occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. For example, the presentinvention provides a compound having the formula:

In another aspect the present invention provides a benzylatedCP-80,633-A or analog thereof compound of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from nitro, R⁴, NR⁴ _((q)),and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, in atleast one occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. In a preferred embodiment, notmore than four of the R₃ groups are hydrogen. For example, the presentinvention provides a compound having the formula:

In another aspect the present invention provides a benzylatedAROFYLLINE™ or analog thereof of the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴, NR⁴_((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. Optionally, in atleast one occurrence, R³ is halogen or OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. For example, thepresent invention provides a benzylated AROFYLLINE™ or analog thereofcompound having the formulae:

In another aspect the present invention provides a benzylatedCIPAMFYLLINE™ or analog thereof compound of the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. For example, thepresent invention provides a benzylated CIPAMFYLLINE™ or analog thereofcompound of the formula:

As another example, the present invention provides a benzylatedCIPAMFYLLINE™ or analog thereof compound of the formula:

In addition to the above-mentioned method for improving the therapeuticratio of PDE4 inhibitors through reduction or elimination of emetogenicproperties while allowing retention of PDE activity, and the compoundsof the present invention, the present invention also provides forinventive pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier, diluent orexcipient. Furthermore, the present invention provides various methodsfor treating and/or preventing various biological, e.g., medical,conditions, where those methods employ a compound of the presentinvention, or a pharmaceutical composition of the present invention.Those methods for treating and/or preventing various biologicalconditions include the following.

A method for treating or preventing an inflammatory condition or diseasein a patient, comprising administering to the patient in need thereof anamount of a benzylated PDE4 inhibitor, where the amount is effective totreat or prevent the inflammatory condition or disease of the patient,and where the benzylated PDE4 inhibitor is prepared by a benzylationmethod described herein. In addition, the present invention provides amethod for treating or preventing an inflammatory condition or diseasein a patient, comprising administering to the patient in need thereof anamount of a benzylated compound as described herein, where the amount iseffective to treat or prevent the inflammatory condition or disease ofthe patient. In one aspect, the PDE4 inhibitor inhibits an enzymeselected from phosphodiesterase 4 A, B, C or D or any combinationthereof including all splice variants of PDE4 A, B, C and D. In variousaspects, the inflammatory condition or disease is an autoimmunecondition or disease; or involves acute or chronic inflammation of boneand/or cartilage compartments of joints; or is an arthritis selectedfrom rheumatoid arthritis, gouty arthritis or juvenile rheumatoidarthritis; or is asthma; or is associated with the disregulation ofT-cells; or the inflammatory condition or disease is multiple sclerosis;or the inflammatory condition or disease is pulmonary sarcadosis; or theinflammatory condition or disease is ocular inflammation or allergy; orthe inflammatory condition or disease is an inflammatory bowel disease,where the inflammatory bowel disease may be Crohn's disease orulcerative colitis; or the inflammatory condition or disease is aninflammatory cutaneous disease, where the inflammatory cutaneous diseasemay be psoriasis or dermatitis; or the inflammatory condition or diseaseis chronic obstructive pulmonary disease (COPD), bronchitis, emphysemaor acute respiratory distress syndrome (ARDS). In another aspect, theinflammatory condition or disease is associated with elevated levels ofinflammatory cytokines. In various aspects, the inflammatory cytokine isIL-2, IL-4 or IL-5; or the inflammatory cytokine is IFN-γ; or theinflammatory cytokine is TNF-α.

A method for treating or preventing a disease or condition in a patient,where the disease or condition is associated with pathologicalconditions that are modulated by inhibiting enzymes associated withsecondary cellular messengers, the method comprising administering tothe patient in need thereof an amount of a benzylated PDE4 inhibitor,wherein the amount is effective to treat or prevent a disease orcondition associated with pathological conditions that are modulated byinhibiting enzymes associated with secondary cellular messengers, andwherein the benzylated PDE4 inhibitor is prepared by a benzylationprocess according to the present invention. In addition, the presentinvention provides a method for treating or preventing a disease orcondition in a patient, where the disease or condition is associatedwith pathological conditions that are modulated by inhibiting enzymesassociated with secondary cellular messengers, the method comprisingadministering to the patient in need thereof an amount of a benzylatedcompound according to the present invention, or a pharmaceuticalcomposition containing a benzylated compound according to the presentinvention, wherein the amount is effective to treat or prevent a diseaseor condition associated with pathological conditions that are modulatedby inhibiting enzymes associated with secondary cellular messengers. Invarious aspects, the enzyme is a cyclic AMP phosphodiesterase; or theenzyme is phosphodiesterase 4.

A method of treating or preventing transplant rejection in a patient,the method comprising administering to the patient in need thereof anamount of a benzylated PDE4 inhibitor, where the amount is effective totreat or prevent transplant rejection in the patient, and wherein thebenzylated PDE4 inhibitor is prepared by a benzylation process accordingthe present invention. In addition, the present invention provides amethod of treating or preventing transplant rejection in a patient, themethod comprising administering to the patient in need thereof an amountof a benzylated compound according to the present invention, or acomposition comprising a compound according to the present invention anda pharmaceutically acceptable carrier, diluent and excipient, where theamount is effective to treat or prevent transplant rejection in thepatient. In one aspect the rejection is due to graft versus hostdisease.

A method of treating or preventing uncontrolled cellular proliferationin a patient, the method comprising administering to the patient in needthereof an amount of a benzylated PDE4 inhibitor, where the amount iseffective to treat or prevent uncontrolled cellular proliferation in thepatient, and wherein the benzylated PDE4 inhibitor is prepared by aprocess according to the present invention. In addition, the presentinvention provides a method of treating or preventing uncontrolledcellular proliferation in a patient, the method comprising administeringto the patient in need thereof an amount of a benzylated compoundaccording to the present invention, or a composition comprising abenzylated compound according to the present invention and apharmaceutically acceptable carrier, diluent or excipient, where theamount is effective to treat or prevent uncontrolled cellularproliferation in the patient. In one aspect, the uncontrolled cellularproliferation is caused by a cancer selected from leukemia and solidtumors.

A method of treating or preventing conditions associated with thecentral nervous system (CNS) in a patient, the method comprisingadministering to the patient in need thereof an amount of a benzylatedPDE4 inhibitor, where the amount is effective to treat or preventconditions associated with the central nervous system (CNS) in thepatient, and wherein the benzylated PDE4 inhibitor is prepared by aprocess according to the present invention. In addition, the presentinvention provides a method of treating or preventing conditionsassociated with the central nervous system (CNS) in a patient, themethod comprising administering to the patient in need thereof an amountof a benzylated compound according to the present invention, or acomposition comprising a benzylated compound according to the presentinvention and a pharmaceutically acceptable carrier, diluent orexcipient, where the amount is effective to treat or prevent conditionsassociated with the central nervous system (CNS) in the patient. In oneaspect, the condition associated with the central nervous system (CNS)is depression. In another aspect, the condition is long-term memoryostentation and learning enhancement.

A method of treating or preventing diseases in a patient, the diseaseassociated with viral infection, the method comprising administering tothe patient in need thereof an amount of a benzylated PDE4 inhibitor,where the amount is effective to treat or prevent diseases associatedwith viral infection in the patient, and wherein the benzylated PDE4inhibitor is prepared by a process according to the present invention.In addition, the present invention provides a method of treating orpreventing diseases in a patient, the disease associated with viralinfection, the method comprising administering to the patient in needthereof an amount of a benzylated compound according to the presentinvention, or a composition comprising a pharmaceutically acceptablecarrier, diluent or excipient in combination with a benzylated compoundof the present invention, where the amount is effective to treat orprevent diseases associated with viral infection in the patient. In oneaspect, the viral infection is due to the human immunodeficiency virus(HIV) and the disease is acquired immunodeficiency syndrome (AIDS).

A method of treating or preventing diseases in a patient, the diseaseassociated with infection by a parasite, the method comprisingadministering to the patient in need thereof an amount of a benzylatedPDE4 inhibitor, where the amount is effective to treat or preventdiseases associated with infection of the patient by a parasite, andwherein the benzylated PDE4 inhibitor is prepared by a process accordingto the present invention. In another aspect, the present inventionprovides a method of treating or preventing diseases in a patient, thedisease associated with infection by a parasite, the method comprisingadministering to the patient in need thereof an amount of a benzylatedcompound according to the present invention, or a composition comprisinga pharmaceutically acceptable carrier, diluent or excipient incombination with a benzylated compound of the present invention, wherethe amount is effective to treat or prevent diseases associated withinfection of the patient by a parasite. In one aspect, the parasiticinfection is due to the trypanosome Bruce and the disease is Africansleeping sickness disease.

A method of treating or preventing cystic fibrosis in a patient, themethod comprising administering to the patient in need thereof an amountof a benzylated PDE4 inhibitor, where the amount is effective to treator prevent cystic fibrosis in the patient, where the amount is effectiveto treat or prevent cystic fibrosis, and wherein the benzylated PDE4inhibitor is prepared by a benzylation process according to the presentinvention. In addition, the present invention provides a method oftreating or preventing cystic fibrosis in a patient, the methodcomprising administering to the patient in need thereof an amount of abenzylated compound according to the present invention, or a compositioncomprising a pharmaceutically acceptable carrier, diluent or excipientin combination with a benzylated compound of the present invention,where the amount is effective to treat or prevent cystic fibrosis.

DETAILED DESCRIPTION OF THE INVENTION

It has been surprisingly discovered that compounds exhibiting PDE4inhibitory activity and emetogenic effects will exhibit reducedemetogenic effects when the compound contains certain chemicalsubstitution, and in particular certain chemical substitution includinga benzyl group.

Definitions

As used herein, and unless otherwise specified, a benzyl group (Bzl,sometimes referred to as Bn) refers to a group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,and when a numeral is carbon then that numeral may be substituted withan organic or inorganic group.

In one aspect, a benzyl group (Bzl) refers to a group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In one aspect, a benzyl group (Bzl) refers to a group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 4carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², and OR² wherein and R² at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, phenyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the phenyl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In one aspect, a benzyl group (Bzl) refers to a group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat at least one R¹ is OR².

In one aspect, a benzyl group (Bzl) refers to a group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 is carbon;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat at least one R¹ is halogen.

In one embodiment, each of the aromatic ring atoms of the benzyl groupis a carbon atom, so that the benzyl group has the formula

wherein n is 0, 1, 2, 3 or 4, and independently at each occurrence,

R¹ is selected from halogen, nitro, R², NR² _((m)), and OR² wherein m=0,1, 2, or 3 and R² is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In any of the above embodiments, in a further embodiment of the presentinvention, n is 1, 2 or 3 and in at least one occurrence R¹ is halogen.

In a compound as disclosed herein, when any variable occurs more thanone time in any constituent or in a benzylated compound, its definitionon each occurrence is independent of its definition at every otheroccurrence. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Thecompounds useful in the methods and compositions of the presentinvention, as well as the compounds of the present invention, may haveasymmetric centers and occur as racemates, racemic mixtures and asindividual diastereomers, or enantiomers with all isomeric forms beingincluded in the present invention. A racemate or racemic mixture doesnot imply a 50:50 mixture of stereoisomers. Also, unless otherwiseindicated, the terms “a” and “an” refer to one, or more than one, of theindicated items. For example, “a compound” includes one and more thanone compound, and “an” isomer refers to one and more than one isomer.

In the benzylated compounds, a salt is preferably a pharmaceuticallyacceptable salt, where salts includes acid addition salts and baseaddition salts. A “pharmaceutically acceptable salt” and “salts thereof”means organic or inorganic salts of the pharmaceutically importantmolecule. A pharmaceutically acceptable salt may involve the inclusionof another molecule such as an acetate ion, a succinate ion or othercounterion. The counterion may be any organic or inorganic moiety thatstabilizes the charge on the parent compound. Furthermore, apharmaceutically important organic molecule may have more than onecharged atom in its structure. Situations where multiple charged atomsare part of the molecule may have multiple counterions. Hence, themolecule of a pharmaceutically acceptable salt may contain one or morethan one charged atoms and may also contain, one or more than onecounterion. The desired charge distribution is determined according tomethods of drug administration. Examples of pharmaceutically acceptablesalts are well known in the art but, without limiting the scope of thepresent invention, exemplary presentations can be found in thePhysician's Desk Reference, The Merck Index, The Pharmacopoeia andGoodman & Gilman's The Pharmacological Basis of Therapeutics.

Acid addition salts refer to those salts formed from benzylatedcompounds of the present invention and inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and/or organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

Base addition salts include those salts derived from benzylatedcompounds of the present invention and inorganic bases such as sodium,potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper,manganese, aluminum salts and the like. Suitable salts include theammonium, potassium, sodium, calcium and magnesium salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine,arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine,ethylenediamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, and the like.

“Alkoxy” refers to alkyl-O—, where “O” represents oxygen and alkyl isdefined below.

“Alkoxyalkyl” refers to alkyl¹-O-alkyl²-, where “O” represents oxygenand alkyl¹ represents the alkoxy portion, i.e., alkyl¹-O is alkoxy,while alkyl² represents the alkyl portion of the alkoxyalkyl group. Inan alkoxyalkyl group, each of alkyl¹ and alkyl² is an alkyl group asdefined below, with the comment that alkyl¹ is monovalent as it has oneopen valence site that is bound to oxygen, while alkyl² is divalent, asit is bound to both oxygen and the remainder of the molecule.

“Alkyl” refers to an acyclic chain of carbon atoms that may be branchedor unbranched (linear). Methyl, ethyl, propyl (including n-propyl andiso-propyl) butyl (including n-butyl, iso-butyl, sec-butyl, andt-butyl), pentyl (including numerous isomers) and hexyl (includingnumerous isomers) are alkyl groups having 1 to 6 carbon atoms (commonlyreferred to as lower alkyl groups), and are exemplary of alkyl groups ofthe invention. As referred to herein, an alkyl group may haveunsaturation between any two carbons, i.e., the alkyl group may havedouble and/or triple bonds. Thus, the term alkyl encompasses alkenylgroups, which are unsaturated aliphatic groups having at least onedouble bond, as well as alkynyl groups, which are unsaturated aliphaticgroups which may be either straight- or branched-chain and have one ormore triple bonds. In various embodiments the alkyl groups have no morethan about 20 carbons atoms, or no more than about 18, or 16, or 14, or12, or 10 carbons atoms, and may be ethyl, propynyl, 4-methylpentynyland so on, and structural isomers thereof. In addition, the term alkylencompasses monovalent as well as polyvalent alkyl groups, where methyl(CH₃—) is an exemplary monovalent alkyl group, while methylene (—CH₂—)is an exemplary polyvalent, and more specifically a divalent alkylgroup. In one embodiment, alkyl excludes methyl. In another embodiment,the alkyl group has at least 3 carbon atoms.

“Alkylamide” refers to an amide group wherein either or both of thecarbon and nitrogen atoms are bonded to alkyl group(s).

“Alkylcarboxyl” refers to a divalent alkyl group wherein one of the openvalence sites is bonded to a carboxyl group, while the remaining openvalence site is bonded to the remainder of the molecule.

“Alkylcarboxylate” refers to a divalent alkyl group wherein one of theopen valence sites is bonded to a carboxylate group, while the remainingopen valence site is bonded to the remainder of the molecule.

“Alkylcycloalkyl” refers to a cycloalkyl group that is bonded both to analkyl group and to the remainder of the molecule. Each of alkyl andcycloalkyl are defined herein.

“Amide” refers to a group of the formula

where the amide group may be joined to the remainder of the moleculethrough either the carbonyl group or the nitrogen atom.

“Aryl” refers to an aromatic hydrocarbon ring system. The ring systemmay be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.).In various embodiments, the monocyclic aryl ring is C5-C10, or C5-C7, orC5-C6, where these carbon numbers refer to the number of carbon atomsthat make up the ring system. A C6 ring system, i.e., a phenyl ring, isa preferred aryl ring. In various embodiments, the polycyclic ring is abicyclic aryl ring, where preferred bicyclic aryl rings are C8-C12, orC9-C10. A naphthyl ring, which has 10 carbon atoms, is a preferredpolycyclic aryl ring. Aryl rings may be substituted or unsubstituted. Inone embodiment, the aryl ring is unsubstituted. In another embodiment,the aryl ring is substituted with 1 substituent (i.e., the aryl ring ismonosubstituted), or 1-2 substituents, or 1-3 substituents, or 1-4substituents, etc.

“Carboxylate” refers to a group of the formula

i.e., —COO⁻, where there is a positively charged counterion present.

“Carboxyl” or “Carboxylic acid” refers to a protonated carboxylate.

“Cycloalkyl” refers to a cyclic alkyl group. Suitable cycloalkyl groupsinclude, for example, cyclohexyl, cyclopropyl, cyclopentyl, andcycloheptyl. Cycloalkenyl is an example of a cycloalkyl group, wheresuitable cycloalkenyl groups include, for example, cyclopentenyl andcyclohexenyl.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Heteroalkyl” refers to a saturated or unsaturated, straight orbranched, chain containing carbon and at least one heteroatom. Theheteroalkyl group may, in various embodiments, have one heteroatom, or1-2 heteroatoms, or 1-3 heteroatoms, or 1-4 heteroatoms. Heteroalkylchains may contain from 1 to 18 (i.e., 1-18) member atoms (carbon andheteroatoms) in the chain, and in various embodiments contain 1-12, or1-6, or 1-4 member atoms. Independently, in various embodiments, theheteroalkyl group has zero branches (i.e., is a straight chain), onebranch, two branches, or more than two branches. Independently, in oneembodiment, the heteroalkyl group is saturated. In another embodiment,the heteroalkyl group is unsaturated. In various embodiments, theunsaturated heteroalkyl may have one double bond, two double bonds, morethan two double bonds, and/or one triple bond, two triple bonds, or morethan two triple bonds. Heteroalkyl chains may be substituted orunsubstituted. In one embodiment, the heteroalkyl chain isunsubstituted. In another embodiment, the heteroalkyl chain issubstituted. A substituted heteroalkyl chain may have 1 substituent(i.e., be monosubstituted), or may have 1-2 substituents, or 1-3substituents, or 1-4 substituents, etc. Exemplary heteroalkyl groupsinclude esters (—C(═O)—OR) and ketones (—C(═O)—). In another embodiment,the heteroalkyl group is not substituted.

“Heteroaryl” is an aromatic ring system or a semi-aromatic system ofrings or a pseudo aromatic ring or rings containing carbon and at leastone heteroatom in at least one of the rings. The heteroaryl group may,in various embodiments, have one heteroatom, or 1-2 heteroatoms, or 1-3heteroatoms, or 1-4 heteroatoms in the ring. The heteroaryl group mayfurther include more than one ring system, which in various embodimentsmay include one heteroatom or 1-2 heteroatoms, or 1-3 heteroatoms, or 1heteroatom in each ring system, or 1-4 heteroatoms in each ring system.The heteroaryl group which comprises more than one ring system may, invarious embodiments have one or more than one of the ring systemsaromatic. Heteroaryl rings may be monocyclic or polycyclic, where thepolycyclic ring may contain fused, spiro or bridged ring junctions. Inone embodiment, the heteroaryl is selected from monocyclic and bicyclic.Monocyclic heteroaryl rings may contain from about 5 to about 10 memberatoms (carbon and heteroatoms), preferably from 5-7, and most preferablyfrom 5-6 member atoms in the ring. Bicyclic heteroaryl rings may containfrom about 8-12 member atoms, or 9-10 member atoms in the ring. Theheteroaryl ring may be unsubstituted or substituted. In one embodiment,the heteroaryl ring is unsubstituted. In another embodiment, theheteroaryl ring is substituted. The substituted heteroaryl ring maycontain 1 substituent, or 1-2 substituents, or 1-3 substituents, or 1-4substituents, etc. Exemplary heteroaryl rings include benzofuran,benzothiophene, furan, imidazole, indole, isothiazole, oxazole,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,quinoline, thiazole and thiophene. In one embodiment, the heteroarylgroup does not have any substituents.

“Heteroatom” is a nitrogen, sulfur, oxygen, or silicon atom. Groupscontaining more than one heteroatom may contain different heteroatoms.

“Heterocycloalkyl” refers to a saturated or unsaturated, monocyclic orpolycyclic (e.g., bicyclic, tricyclic, etc.) ring containing carbon andat least one heteroatom. Heterocyclic aliphatic rings are not aromaticper se but may be pseudo-aromatic and/or readily be made aromaticthrough methods known in the art. The heterocyclic aliphatic ring may,in various embodiments, have one heteroatom, or 1-2 heteroatoms, or 1-3heteroatoms, or 1-4 heteroatoms, etc. In one embodiment, theheterocyclic aliphatic ring is monocyclic, where the monocyclic ring mayhave 3-10, or 4-7, or 5-6 member atoms. In another embodiment, theheterocyclic aliphatic ring is polycyclic, where in various embodiments,the ring may be bicyclic, or may be tricyclic, or may be either bicyclicor tricyclic. A polycyclic ring system may have one or more fused, spiroor bridged ring systems. The polycyclic heterocyclic aliphatic ringsystem may have 6-12, or 9-10 member atoms. The heterocyclic ring may beunsubstituted or substituted. In one embodiment, the heterocyclic ringis unsubstituted. In another embodiment, the heterocyclic ring issubstituted. The substituted heterocyclic ring may contain 1substituent, or 1-2 substituents, or 1-3 substituents, or 1-4substituents, etc. Exemplary heterocyclic aliphatic rings includepiperazyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl andpiperidyl. In another embodiment, the heterocycloalkyl is notsubstituted.

“Hydroxyalkyl” refers to an alkyl group that is bonded to both a hydroxy(HO—) group and to the remainder of the molecule. In other words, agroup that may be represented as HO-alkyl-.

“Indanyl” refers to an indane group, i.e., a group of the structure

wherein one of the carbons of the indane group is bonded to theremainder of the molecule.

“Phenoxyalkyl” refers to phenyl-O-alkyl-, where “phenyl-O” is thephenoxy portion of the phenoxyalkyl group, and “alkyl” is the alkylportion of the phenoxyalkyl group. The alkyl portion of the phenoxyalkylgroup is defined above, with the comment that in a phenoxyalkyl radical,the alkyl group is divalent.

“Phenylalkyl” refers to phenyl-alkyl-, where “pheny” is the phenylportion of the phenylalkyl group, and “alkyl” is the alkyl portion ofthe phenylalkyl group. The alkyl portion of the phenylalkyl group isdefined above, with the comment that in a phenylalkyl radical, the alkylgroup is divalent.

“Polycycloalkyl” refers to an arrangement of carbon atoms wherein atleast one carbon atom is a part of at least two separately identifiablerings. The polycycloalkyl group may contain bridging between two carbonatoms, where bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl,bicyclo[5,2.0]nonyl, tricycl[2.2.1.0¹]heptyl, norbornyl and pinanyl arerepresentative examples. The polycycloalkyl group may contain one ormore fused ring systems, where decalinyl (radical from decalin) andperhydroanthracenyl are representative examples. The polycycloalkylgroup may contain a spiro union, in which a single atom is the onlycommon member of two rings. Spiro[3.4]octyl, spiro[3.3]heptyl andspiro[4.5]decyl are representative examples. Polycycloalkyl groupshaving 6, 7, 8 or 9 carbon atoms, i.e., C₆-C₉polycycloalkyl, are apreferred polycycloalkyl group of the present invention.

In describing the present invention, the following abbreviations may beused, where these abbreviations have the meaning as indicated in thefollowing Table.

Abbreviation Full name 5-ASA 5-aminosalicylic acid Ab Antibody ABTS2,2′-azino-di-[3-ethylbenzthiazoline sulphonate] ACD Acid citratedextrose AcOH Acetic Acid ACVP American College of Veterinary PracticeANOVA Analysis of Variance Ar Argon BCR-ABL Oncogene in chromosome 9:22translocation in CML BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBn Benzyl BnBr Benzyl Bromide BOC tert-Butoxycarbonyl cAMP Cyclicadenosine 3′–5′-monophosphate cat Catalytic CD Cluster designation CFAComplete Freund's adjuvant cGMP Cyclic guanosine 3′–5′-monophosphate CIACollagen Induced Arthritis CLL Chronic lymphocytic leukemia CML Chronicmyelogenous leukemia CNS Central Nervous System Con A Concanavalin A COXCyclooxygenase cPent Cyclopentyl cPentBr Cyclopentyl bromide CRE cAMPresponse element CsA Cyclosporin A DMAP 4-Dimethylaminopyridine DMARDDisease modifying anti-rheumatic drug DMF N,N-Dimethylformamide DMSOdimethylsulfoxide DNA Deoxyriboneucleic acid DNBS 2,4-Dinitrobenzenesulphoric acid dppf 1,1′-Bis(diphenylphosphino)ferrocene dppp 1,3-Bis(diphenylphosphino)propane EC₅₀ Concentration at which a 50% ofmaximum observable effect is noted EDTA Ethylenediaminotetraacetic acidELISA Enzyme-linked immunosorbent assay EtOAc Ethyl acetate EtOH Ethylalcohol FBS Fetal bovine serum FCS Fetal calf serum fMLPFormyl-methionyl leucine phenylalanine g.i. Gastrointestinal H & EHaematoxylin and eosin HARBS High affinity rolipram binding site HBSSHanks Balanced Salt Solution HMPA Hexamethylphosphoramide HPLC Highpressure liquid chromatography i.p. intraperitoneal IBD Inflammatorybowel disease IBMX 3-isobutyl-1-methylxanthine IC Inhibitoryconcentration IC₅₀ Concentration at which 50% inhibition is observed IFAIncomplete Freund's adjuvant IFN-γ Interferon gamma IL Interleukin LAHLithium aluminum hydride LDA Lithium diisopropylamide LN Lymph node LPSlipopolysaccharide LTB4 Leukotriene B4 luc luciferase Me Methyl MeOHMethyl alcohol MHC Major histocompatibility class MLR Mixed lymphocytereaction MPO myeloperoxidase Ms Methanesulfonyl MsCl Methanesulfonylchloride NBS N-Bromosuccinimide n-BuLi n-Butyllithium n-BuSHn-Butanethiol NF-κB Nuclear factor kappa B NSAID Non-steroidalanti-inflammatory drug p.t. Post-transplant PBS Phosphate bufferedsaline Pcc Pigeon cytochrome C PDE Phosphodiesterase PEG Polyethyleneglycol PG Prostaglandin PMS Phenazine methosulfate PMSF Phenyl methylsulfonyl fluoride pTsOH p-Toluenesulfonic acid monohydrate Py PyridineRA Rheumatoid arthritis RF Rheumatoid factor R_(f) Retardation factorROS Reactive oxygen species RPMI Rosewell Park Memorial Institute RTXResiniferitoxin SAR Structure activity relationship TBAFTetrabutylammonium fluoride TBDMS tert-Butyldimethylsilyl TBDMSCltert-Butyldimethylsilyl chloride TCR T-cell receptor TEA TriethylamineTf Trifluoromethanesulfonyl TFA Trifluoroacetic acid Th T helper THFTetrahydrofuran TNBS Trinitrobenzene sulfonic acid TNF-α Tumour necrosisfactor alpha Trolox ® 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylicacid TsOH p-Toluenesulfonic acid monohydrate XTT2,3-bis[2-methoxy-4-nitro-5-sulfo-phenyl]-2H- tetrazolium5-carboxanilide inner salt μM Micro molarMethod of the Present Invention

In one aspect, the present invention is directed to a method forimproving the therapeutic ratio of PDE4 inhibitors through reduction orelimination of emetogenic properties while allowing retention of PDEactivity. The method comprises benzylation of a PDE4 inhibitor, whereinthe benzylation places a benzyl group on a carbon (referred to herein asC-benzylation) or nitrogen (referred to herein as N-benzylation) atom ofa PDE4 inhibitor, to provide a benzylated PDE4 inhibitor. In one aspectof the invention, the benzylation places a benzyl group on a carbon atomof a PDE4 inhibitor. In another aspect of the invention, the benzylationplaces a benzyl group on a nitrogen atom of a PDE4 inhibitor. In oneaspect of the invention, the benzylation places a benzyl group on acarbon atom or a nitrogen atom of a PDE4 inhibitor. In another aspect,the benzylation places two benzyl groups on a PDE4 inhibitor.

The addition of a benzyl group to a PDE4 inhibitor is readilyaccomplished by reacting the PDE4 inhibitor (or a protected versionthereof) with a benzylating agent (or a protected version thereof) underconditions such that the benzylating agent forms a covalent bond to acarbon or nitrogen atom of the PDE4 inhibitor. As used herein, abenzylating agent includes a benzyl group as defined herein having aleaving group attached to the methylene carbon of the benzyl group,i.e., a leaving group alpha to the aromatic ring. Suitable leavinggroups include halogens, e.g., chloride and bromide, and sulfonates,e.g., mesylate and tosylate. Such a benzylating agent has the generalformula as shown below.

wherein n is 0, 1, 2, 3 or 4, and independently at each occurrence,

R¹ is selected from halogen, nitro, R², NR² _((m)), and OR² wherein m=0,1, 2, or 3 and R² is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

Reaction conditions whereby a PDE4 inhibitor will react with abenzylating agent so as to form a benzylated PDE4 inhibitor includebasic conditions. In the presence of basic conditions, the one or moreextractable hydrogens of the PDE4 inhibitor will react with base so thatthe PDE4 inhibitor forms the corresponding nucleophilic anion. Thenucleophilic center will then react with the benzylating agent withconcomitant displacement of the leaving group, so as to join the PDE4inhibitor to the benzyl group. Benzylation chemistry in general is wellknown in the art, and may be applied to the goal of henzylating PDE4inhibitors according to the present invention.

The basic conditions are created by combining the PDE4 inhibitor with abase, typically in a suitable solvent. Suitable bases must be selectedbased on the acidity of the hydrogen atom being removed from the PDE4inhibitor. That is, a relatively more basic compound must be employedwhen the hydrogen being removed from the PDE4 inhibitor is relativelyless extractable. Suitable bases for most instances include sodiumhydride, potassium hydride, metal amine salts such as lithium aminesalts, e.g., lithium diisopropylamide, and sodium amine salts, lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodium alkoxide orpotassium alkoxide where alkoxide refers to O-alkyl and alkyl is definedherein.

Scheme 1 depicts general synthetic methodology that may be used for theintroduction of a benzyl group at a location alpha to a carbonyl group.Scheme 1 depicts this methodology with an ester-containing molecule, andmore specifically with a lactone, however, the same methodology may beused when the carbonyl group is part of a lactam or otheramide-containing molecule, or when the carbonyl group is part of anon-lactone ester group or ketone group or carboxylic acid group. Asdiscussed in more detail below, this general methodology may be appliedto a carbonyl-containing compound that has substitution and/or when thebenzylating agent has substitution.

Although Scheme 1 illustrates one methodology that may be employedaccording to the present invention using an unsubstituted benzylationagent (and, more specifically, benzyl bromide, abbreviated as BnBr) toafford a benzylated product, any number of substituted benzylationagents can be used to generate a benzylated product with varioussubstitution patterns on the benzyl ring. Substituted benzyl bromidesare available commercially or may be generated from the correspondingsubstituted benzyl alcohol, benzaldehyde, benzoic acid or benzoic ester.

For example, substituted benzyl bromides can be prepared as outlined inScheme 2. Thus, treatment of commercially available benzyl alcohol 1with benzyl bromide and potassium carbonate in toluene gives thecorresponding benzyloxy derivative 2, which is treated, withoutpurification, with PBr₃ in diethyl ether to give the desired bromidecompound 3 in quantitative yield. Any number of compounds related tocompound 3 could be produced using similar methodology but starting witha different substituted benzyl alcohol.

Substituted benzyl bromide compounds can also be prepared fromcommercially available substituted benzaldehydes, benzoic acids andbenzoic esters by first converting these compounds to the correspondingalcohol. Benzyl aldehydes may be reduced to the corresponding alcohol bystandard reducing conditions, e.g., sodium borohydride in methanol. Insome instances, it may be necessary to protect other functionality onthe benzyladehyde compound in order that the other functionality is notundesirably modified by the reduction conditions.

It may be necessary to protect certain reactive groups present in thePDE4 inhibitor from the benzylation reaction. Suitable protecting groupsand methods for their use are described in “Protective Groups in OrganicSynthesis”, 3^(rd) Edition, by Greene, T. W. and Wuts, P. G. M., JohnWiley & Sons, 1999.

As for selection of the PDE4 inhibitor, many of these are known in theart and may be advantageously benzylated according to the presentinvention. Suitable PDE4 inhibitors include, without limitation,ROLIPRAM™, ARIFLO™, WAY-PDA-641, Ro-20-1724, RP 73401, CP-80,633-A,AROFYLLINE™, and CIPAMFYLLINE™. In a preferred embodiment, benzylationof a PDE4 inhibitor occurs by placing a benzyl group on a carbon atom ofthe PDE4 inhibitor. PDE4 inhibitors suitable for benzylation on a carbonatom include, without limitation, ROLIPRAM™ and ARIFLO™. In anotheraspect, the present invention employs PDE4 inhibitors suitable forbenzylation on a nitrogen atom, where such PDE4 inhibitors include,without limitation, WAY-PDA-641, Ro-20-1724, RP 73401, CP-80,633-A,AROFYLLINE™, and CIPAMFYLLNE™. The following literature references, inaddition to those provided in the Background of the presentspecification, describe various PDE4 inhibitors and methodology toidentify a PDE4 inhibitor: PCT International Publication No. WO92/12961;J. Med. Chem. 1997, 40, 1417-1421; Organic Process Research &Development 1998, 2, 157-168; J. Med. Chem., 1994, 37, 1696-1703; andU.S. Pat. Nos. 5,124,455; 5,814,651; 3,636,039; 4,308,278; 5,223,504;5,734,051.

In one aspect of the present invention, the benzylated PDE4 inhibitorcomprises a benzyl group, and independently of the benzyl group thebenzylated PDE4 inhibitor further comprises the group

wherein p is 5; and R³ at each occurrence is independently selected fromhalogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In one aspect ofthe invention R³ is OR⁴ in at least one occurrence wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl.C-Benzylation of PDE4 Inhibitors

In one aspect of the invention, the benzylation may provide a benzylgroup attached to a carbon atom of the PDE4 inhibitor. In variousembodiments of this aspect of the invention, the benzyl group beingadded to the PDE4 inhibitor has one of the following definitions:

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; or

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 4carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², and OR² wherein and R² at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, phenyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR² group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the phenyl portion of an R² group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; or

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the-amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat either (a) at least one R¹ is OR², or (b) the benzyl ring containsat least two R¹ groups that are not hydrogen.

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat R₁ is hydrogen at either 1, 2, or 3 occurrences of n, but not 4 or5 occurrences.

In one aspect of the invention, the PDE4 inhibitor is ROLIPRAM™ or ananalog thereof. In one embodiment, the benzylated ROLIPRAM™ or analogthereof according to the inventive method has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; A is selected from a direct bond, optionally substitutedC₁-C₅alkylene, optionally substituted C₂-C₅alkenyl and optionallysubstituted phenylene; p is 5; and R³ at each occurrence isindependently selected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴wherein q=0, 1, 2, or 3 and R⁴ at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl,heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R⁴ group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the aryl portion of anR⁴ group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy orhalogen. In one aspect of the invention R³ is OR⁴ in at least oneoccurrence wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and,C₆-C₉polycycloalkyl. In another embodiment, A is a direct bond; p is 1,2, or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Inanother embodiment, the benzylated ROLIPRAM™ or analog thereof has theformula:

In a different aspect, the PDE4 inhibitor undergoing the benzylationreaction of the present invention is ARIFLO™ or an analog thereof. Inone embodiment, the benzylated ARIFLO™ or analog thereof produced thepresent invention has the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; R⁶ isselected from H, positively charged species, and C₁-C₈alkyl; and R⁵ isselected from H, halogen, nitro, cyano, C₁-C₈alkyl, and C₁-C₈alkoxy. Inone aspect of the invention R³ is OR⁴ in at least one occurrence whereinR⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl; R⁶ is selected from H, positively charged species,and C₁-C₈alkyl; and R⁵ is selected from H, halogen, nitro, cyano,C₁-C₈alkyl, and C₁-C₈alkoxy. In one embodiment, p is 1, 2 or 3; and inat least one occurrence, R³ is OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl, R⁶ is selected fromH and positively charged species; and R⁵ is selected from H, halogen,nitro, cyano, C₁-C₃alkyl, and C₁-C₃alkoxy. In another embodiment, thebenzylated ARIFLO™ or analog thereof has the formula

In another embodiment, the benzylated ARIFLO™ or analog thereof has theformula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl, R⁶ is selected from H and positively chargedspecies; and R⁵ is selected from H, halogen, cyano, C₁-C₃alkyl, andC₁-C₃alkoxy. In one embodiment, the benzylated ARIFLO™ or analog thereofhas the formula

N-Benzylation of PDE4 Inhibitors

In one aspect of the invention, the benzylation may provide a benzylgroup attached to a nitrogen atom of the PDE4 inhibitor. In a preferredembodiment of this aspect of the invention, the benzyl group has thefollowing definition:

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat either (a) at least one R¹ is OR², or (b) the benzyl ring containsat least two R¹ groups that are not hydrogen.

A benzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 is carbon, n is 5 and R¹at each occurrence is independently selected from halogen, nitro, R²,NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

A benzyl group (Bzl) of the formula

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R² group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the phenyl portion ofan R² group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxyor halogen.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat either (a) at least one R¹ is OR², or (b) the benzyl ring containsat least two R¹ groups that are not hydrogen.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 is carbon;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisothat R₁ is hydrogen at either 1, 2, or 3 occurrences of n, but not 4 or5 occurrences.

In another aspect, the benzylated PDE4 inhibitor comprises at least onebenzyl group (Bzl) of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogenand OR² wherein R² at each occurrence is independently selected from Hand C₁-C₈alkyl; with the provisos that the benzyl ring contain no morethan three hydrogen substituents and no more than one methoxysubstituent.

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is ROLIPRAM™ or analogthereof and the N-benzylated ROLIPRAM™ has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; A is selected from a direct bond, optionally substitutedC₁-C₅alkylene, optionally substituted C₂-C₅alkenyl and optionallysubstituted phenylene; p is 5; and R³ at each occurrence isindependently selected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴wherein q=0, 1, 2, or 3 and R⁴ at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl,heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R⁴ group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the aryl portion of anR⁴ group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy orhalogen. In one embodiment, A is a direct bond; p is 1, 2, or 3; and inat least one occurrence, R³ is OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. In one embodiment,benzylated ROLIPRAM™ or analog thereof has the formula

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is WAY-PDA-641 or ananalog thereof. See, e.g. U.S. Pat. No. 5,124,455. In one embodiment,the benzylated WAY-PDA-641 or analog thereof has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In another embodiment, the benzylated WAY-PDA-641or analog thereof has the formula:

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is Ro-20-1724 or ananalog thereof. See, e.g., U.S. Pat. Nos. 3,636,039 and 4,308,278. Inone embodiment, the benzylated Ro-20-1724 or analog thereof has theformula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₅-C₉bicycloalkyl. In one embodiment, the benzylated Ro-20-1724 oranalog thereof has the formula:

In another embodiment, the benzylated Ro-20-1724 or analog thereof hasthe formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In another embodiment, the benzylated Ro-20-1724 oranalog thereof has the formula:

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is RP 73401 or an analogthereof. See, e.g., PCT International Publication No. 92/12961; OrganicProcess Research & Development 1998, 2, 157-168; and J. Med. Chem. 1994,37, 1696-1703. In one embodiment, the benzylated RP 73401 or analogthereof has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In another embodiment, the benzylated RP 73401 oranalog thereof has the formula:

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is CP-80,633-A or ananalog thereof. See, e.g., U.S. Pat. No. 5,814,651. In one embodiment,the benzylated CP-80,633-A or analog thereof has the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons, in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ is OR⁴wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl, andC₆-C₉polycycloalkyl. In one embodiment, the benzylated CP-80,633-A oranalog thereof has the formula:

A benzylated compound as disclosed herein includes stereoisomers inadmixture and isolated form. Shown below are two stereoisomers ofbenzylated CP-80,633-A according to the invention.

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is AROFYLLINE™ or ananalog thereof. In one embodiment, the benzylated AROFYLLINE™ or analogthereof has the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In oneembodiment, p is 1, 2 or 3; and in at least one occurrence, R³ ishalogen or OR⁴ wherein R⁴ is selected from C₁-C₈alkyl, C₃-C₇cycloalkyl,and C₆-C₉polycycloalkyl. In one embodiment, the benzylated AROFYLLINE™or analog thereof has the formula:

while in another embodiment, the benzylated AROFYLLINE™ or analogthereof has the formula:

In one aspect of the present invention where benzylation provides anN-benzylated PDE4 inhibitor, the PDE4 inhibitor is CIPAMFYLLINE™ or ananalog thereof. In one embodiment, the benzylated CIPAMFYLLINE™ oranalog thereof is selected from the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group.Benzylated PDE4 Inhibitors

In various aspects, the present invention provides the followingspecific benzylated PDE4 inhibitors.

A C-benzylated ROLIPRAM™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; A is selected from a direct bond, optionally substitutedC₁-C₅alkylene, optionally substituted C₂-C₅alkenyl and optionallysubstituted phenylene; p is 5; and R³ at each occurrence isindependently selected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴wherein q=0, 1, 2, or 3 and R⁴ at each occurrence is independentlyselected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in thealkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl,alkylcycloalkyl, hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl,alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl,heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion,phenylaminoalkyl having 2-6 carbons in the alkyl portion and the aminomay be optionally substituted with C₁-C₄alkyl and indanyl; wherein thealkyl portion of an R⁴ group may be optionally substituted with one ormore fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the aryl portion of anR⁴ group may be optionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy orhalogen. In a further embodiment, A is a direct bond; p is 1, 2, or 3;and in at least one occurrence, R³ is OR⁴ wherein R⁴ is selected fromC₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. In a preferredembodiment, R³ at the para position relative to A is alkoxy, and R³ atone meta position is selected from alkyl having at least 3 carbons andalkoxy having at least 3 carbons. In a further embodiment, thebenzylated PDE4 inhibitor has the formula:

A benzylated ARIFLO™ or analog thereof compound of the formulae

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; p is 5; and R³ ateach occurrence is independently selected from halogen, nitro, R⁴, NR⁴_((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at each occurrence isindependently selected from H, C₁-C₈alkyl, alkoxyalkyl having 3-7carbons in the alkoxy portion and 2-4 carbons in the alkyl portion,phenoxyalkyl having 2-6 carbons in the alkyl portion, C₃-C₇cycloalkyl,C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxylate,alkylcarboxylate, carboxyl, alkyl carboxyl, amide, alkylamide, aryl,heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in thealkyl portion and the amino may be optionally substituted withC₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ group may beoptionally substituted with one or more fluorine atoms, hydroxyl orC₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; R⁵ is selected fromH, halogen, cyano, C₁-C₈alkyl, and C₁-C₈alkoxy; and R⁶ is selected fromH, positively charged species, and C₁-C₈alkyl. Optionally, in at leastone occurrence, R³ is OR⁴ wherein R⁴ is selected from C₁-C₈alkyl,C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl; and R⁶ is selected from H andpositively charged species.

In one aspect, the benzylated ARIFLO™ or analog thereof compound has aformula,

In another aspect, the benzylated ARIFLO™ or analog thereof compound hasa formula,

In another aspect, the benzylated ARIFLO™ or analog thereof compound hasa formula,

In another aspect, the benzylated ARIFLO™ or analog thereof compound hasa formula,

In other embodiments, the benzylated ARIFLO™ or analog thereof compoundhas specific stereochemistry. Certain specific stereochemistries areshown below:

In another aspect, the present invention provides an N-benzylatedROLIPRAM™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein

Bzl is a benzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogen,nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 and R² at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen;

A is selected from a direct bond, optionally substituted C₁-C₅alkylene,optionally substituted C₂-C₅alkenyl and optionally substitutedphenylene;

p is 5 and R³ at each occurrence is independently selected from halogen,nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen; with the provisosthat, at the meta position relative to the A group on the R³-substitutedphenyl ring, R³ is alkoxy having at least three carbon atoms, excludingcyclopentyloxy, and at the para position R¹ is not hydrogen.

In a different aspect, the present invention provides an N-benzylatedROLIPRAM™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group of the formula

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms;

n is 5 and R¹ at each occurrence is independently selected from halogenand OR² wherein R² at each occurrence is independently selected from Hand C₁-C₈alkyl; with the provisos that the benzyl ring contain no morethan three hydrogen substituents and no more than one methoxysubstituent;

A is selected from a direct bond, optionally substituted C1-C5alkylene,optionally substituted C²-C⁵alkenyl and optionally substitutedphenylene;

p is 5 and R³ at each occurrence is independently selected from halogen,nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 and R⁴ at eachoccurrence is independently selected from H, C₁-C₈alkyl, alkoxyalkylhaving 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkylportion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.

In a further embodiment, the PDE4 inhibitor is an N-benzylated PDE4inhibitor having the formula

In another aspect, the present invention provides an N-benzylatedWAY-PDA-641 or analog thereof compound of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; and (R³)_(p) is as defined herein. Optionally, p is 1, 2or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ is selectedfrom C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. In a furtherembodiment, the PDE4 inhibitor is an N-benzylated PDE4 inhibitor havingthe formula

In another aspect, the present invention provides an N-benzylatedRo-20-1724 or analog thereof compound of the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from halogen, nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2,or 3 and R⁴ at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl,phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkylhaving 2-6 carbons in the alkyl portion and the amino may be optionallysubstituted with C₁-C₄alkyl and indanyl; wherein the alkyl portion of anR⁴ group may be optionally substituted with one or more fluorine atoms,hydroxyl or C₁-C₈alkoxy; and the aryl portion of an R⁴ group may beoptionally substituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In apreferred embodiment, relative to the methylene bridge to theheterocyclic ring, R³ at the para position is alkoxy, and R³ at a metaposition is alkoxy having at least three carbon atoms. Optionally, p is1, 2 or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₅-C₉bicycloalkyl. Inanother embodiment the invention provides an N-benzylated Ro-20-1724 oranalog thereof compound having the formula

while in another embodiment the invention provides an N-benzylatedRo-20-1724 or analog thereof compound having the formula

while in another embodiment the invention provides an N-benzylatedRo-20-1724 or analog thereof compound having the formula

while in another embodiment the invention provides an N-benzylatedRo-20-1724 or analog thereof compound having the formula

In another aspect, the present invention provides an N-benzylated RP73401 or analog thereof compound of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; and (R³)_(p) is as defined herein. Optionally, p is 1, 2or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ is selectedfrom C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. In oneembodiment, the N-benzylated RP 73401 or analog thereof compound has theformula:

In another aspect, the present invention provides an N-benzylatedCP-80,633-A or analog thereof compound of the formulae:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; p is 5; and R³ at each occurrence is independentlyselected from nitro, R⁴, NR⁴ _((q)), and OR⁴ wherein q=0, 1, 2, or 3 andR⁴ at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R⁴ groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R⁴ group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen. In a preferredembodiment, not more than 4 of the R³ groups are hydrogen. Optionally, pis 1, 2 or 3; and in at least one occurrence, R³ is OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Inone embodiment, the N-benzylated

In one embodiment the N-benzylated CP-80,633-A or analog thereofcompound has the formula:

In another aspect, the present invention provides an N-benzylatedAROFYLLINE™ or analog thereof of the formula:

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group; and (R³)^(p) is as defined above. Optionally, p is 1, 2 or3; and in at least one occurrence, R³ is halogen or OR⁴ wherein R⁴ isselected from C₁-C₈alkyl, C₃-C₇cycloalkyl, and C₆-C₉polycycloalkyl. Inanother embodiment, the N-benzylated AROFYLLINE™ or analog thereof hasthe formula

while in another embodiment the N-benzylated AROFYLLINE or analogthereof has the formula

In another aspect, the present invention provides an N-benzylatedCIPAMFYLLINE™ or analog thereof compound of the formula

and isolated stereoisomers, salts and solvates thereof, wherein Bzl is abenzyl group.Pharmaceutical Compositions

In another embodiment, the present invention provides pharmaceuticalcompositions containing a benzylated compound of the invention, i.e., aC- or N-benzylated compound as described herein and/or made according tothe method of the present invention, in combination with apharmaceutically-acceptable carrier, diluent or excipient. Thesecompositions may be used for the treatment of inflammation or otherconditions as disclosed herein. These compositions may also be formedinto a medicament, which may used in the treatment of, for example,inflammation.

In addition, these compositions are useful as, for example, assaystandards, convenient means of making bulk shipments, or pharmaceuticalcompositions. An assayable amount of a compound of the invention is anamount which is readily measurable by standard assay procedures andtechniques as are well known and appreciated by those skilled in theart. Assayable amounts of a compound of the invention will generallyvary from about 0.001 wt % to about 98 wt % of the entire weight of thecomposition. Inert carriers include any material which does not degradeor otherwise covalently react with a compound of the present invention.Examples of suitable inert carriers are water; aqueous buffers, such asthose which are generally useful in High Performance LiquidChromatography (HPLC) analysis; organic solvents, such as acetonitrile,ethyl acetate, hexane and the like; and pharmaceutically acceptablecarriers.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. Id. at 1449. In addition,antioxidants and suspending agents may be used. Id.

Thus, the present invention provides a pharmaceutical or veterinarycomposition (hereinafter, simply referred to as a pharmaceuticalcomposition) containing a benzylated compound of the invention asdescribed above, in admixture with a pharmaceutically acceptablecarrier. The invention further provides a composition, preferably apharmaceutical composition, containing an effective amount of a compoundof the present invention, as described above, in association with apharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be in anyform which allows for the composition to be administered to a patient.For example, the composition may be in the form of a solid, liquid orgas (aerosol). Typical routes of administration include, withoutlimitation, oral, topical, parenteral, sublingual, rectal, vaginal,intranasal, and inhalation. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Pharmaceutical composition of theinvention are formulated so as to allow the active ingredients containedtherein to be bioavailable upon administration of the composition to apatient. Compositions that will be administered to a patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the presentinvention in aerosol form may hold a plurality of dosage units.

Materials used in preparing the pharmaceutical compositions should bepharmaceutically pure and non-toxic in the amounts used. It will beevident to those of ordinary skill in the art that the optimal dosage ofthe active ingredient(s) in the pharmaceutical composition will dependon a variety of factors. Relevant factors include, without limitation,the type of subject (e.g., human), the particular form of the activeingredient, the manner of administration and the composition employed.

In general, the pharmaceutical composition includes a benzylatedcompound as described herein, in admixture with one or more carriers.The carrier(s) may be particulate, so that the compositions are, forexample, in tablet or powder form. The carrier(s) may be liquid, withthe compositions being, for example, an oral syrup or injectable liquid.In addition, the carrier(s) may be gaseous, so as to provide an aerosolcomposition useful in, e.g., inhalatory administration.

When intended for oral administration, the composition is preferably ineither solid or liquid form, where semi-solid, semi-liquid, suspensionand gel forms are included within the forms considered herein as eithersolid or liquid.

As a solid composition for oral administration, the composition may beformulated into a powder, granule, compressed tablet, pill, capsule,chewing gum, wafer or the like form. Such a solid composition willtypically contain one or more inert diluents or edible carriers. Inaddition, one or more of the following adjuvants may be present: binderssuch as carboxymethylcellulose, ethyl cellulose, microcrystallinecellulose, or gelatin; excipients such as starch, lactose or dextrins,disintegrating agents such as alginic acid, sodium alginate, Primogel,corn starch and the like; lubricants such as magnesium stearate orSterotex; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin, a flavoring agent such as peppermint,methyl salicylate or orange flavoring, and a coloring agent.

When the composition is in the form of a capsule, e.g., a gelatincapsule, it may contain, in addition to materials of the above type, aliquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.

The composition may be in the form of a liquid, e.g., an elixir, syrup,solution, emulsion or suspension. The liquid may be for oraladministration or for delivery by injection, as two examples. Whenintended for oral administration, preferred composition contain, inaddition to the present compounds, one or more of a sweetening agent,preservatives, dye/colorant and flavor enhancer. In a compositionintended to be administered by injection, one or more of a surfactant,preservative, wetting agent, dispersing agent, suspending agent, buffer,stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordigylcerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, cyclodextrin, propylene glycol or othersolvents; antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid composition intended for either parenteral or oraladministration should contain an amount of a compound of the presentinvention such that a suitable dosage will be obtained. Typically, thisamount is at least 0.01% of a compound of the invention in thecomposition. When intended for oral administration, this amount may bevaried to be between 0.001% and about 97% of the weight of thecomposition. Preferred oral compositions contain between about 0.1% andabout 50% of the active compound of the present invention. Preferredcompositions and preparations according to the present invention areprepared so that a parenteral dosage unit contains between 0.1% to 5% byweight of active compound.

The pharmaceutical composition may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, beeswax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of a benzylated compound of the present invention of fromabout 0.01% to about 10% w/v (weight per unit volume).

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol.

The composition may include various materials which modify the physicalform of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the activeingredients. The materials which form the coating shell are typicallyinert, and may be selected from, for example, sugar, shellac, and otherenteric coating agents. Alternatively, the active ingredients may beencased in a gelatin capsule.

The composition in solid or liquid form may include an agent which bindsto the active component(s) and thereby assists in the delivery of theactive components. Suitable agents which may act in this capacityinclude a monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may consist ofgaseous dosage units, e.g., it may be in the form of an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds ofthe invention may be delivered in single phase, bi-phasic, or tri-phasicsystems in order to deliver the active ingredient(s). Delivery of theaerosol includes the necessary container, activators, valves,subcontainers, spacers and the like, which together may form a kit.Preferred aerosols may be determined by one skilled in the art, withoutundue experimentation.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in the treatment of inflammation (including arthritis).

The pharmaceutical compositions may be prepared by methodology wellknown in the pharmaceutical art.

A composition intended to be administered by injection can be preparedby combining a benzylated compound as described herein with water so asto form a solution. A surfactant may be added to facilitate theformation of a homogeneous solution or suspension. Surfactants arecompounds that non-covalently interact with the benzylated compounds ofthe invention so as to facilitate dissolution or homogeneous suspensionof the active compound in the aqueous delivery system.

In a preferred embodiment, a benzylated PDE4 inhibitor according to thepresent invention, or a benzylated PDE4 inhibitor prepared according tothe present invention, has an IC₅₀ of 600 nM (nanomolar) or less, morepreferably 400 nM or less.

Methods for Assessment of PDE4 Activity, HARBS Activity and EmetogenicPotential

Various in vitro tests, which are well known to one of ordinary skill inthe art, may be used to determine whether a particular compound is a PDEinhibitor. Some tests are specific to a particular PDE isozyme orconformer, while other tests are less specific. A few of these tests aredescribed below. The identification of other testing protocols isreadily achieved by reviewing the scientific and patent literature,including Burnouf, C. et al. “Phosphodiesterase 4 Inhibitors” AnnualReports in Medicinal Chemistry, Vol. 33, Chap. 10, pp 91-109, 1998(Bristol, J. A., ed.); Essayan, D. M. “Cyclic NucleotidePhosphodiesterase (PDE) Inhibitors and Immunomodulation” BiochemicalPharmacology 57:965-973, 1999; Souness, J. E. and Foster, M. “Potentialof phospodiesterase type IV inhibitors in the treatment of rheumatoidarthritis” Idrugs 1(5):541-553, 1998; Souness, J. E. et al.“Immunosuppressive and anti-inflammatory effect of cAMPphosphodiesterase (PDE) type 4 inhibitors” Immunopharmacology 47:127-162, 2000; and Torphy, T. J. “Phosphodiesterase Isozymes” Am J.Respir. Crit. Care Med. 157:351-370, 1998, as well as the numerousreferences cited in these articles.

A test compound may be screened for activity against 11 of the majorclasses of mammalian cyclic nucleotide phosphodiesterase (termed PDE 1through 11). These PDE's may use cAMP or cGMP or both cyclic nucleotidesas substrates. The broad specificity PDE inhibitor3-isobutyl-1-methylxanthine (IBMX; Sigma; Catalogue No. 17018) or likecompound may be used as a positive control in most assays. PDE's forsome of the various assays may be fully or partially purified from thefollowing cells/tissues: PDE 1 (bovine heart), PDE 2 (human platelets),PDE 3 (human platelets), PDE4 (human promonocytic U937 cells) and PDE 5(human platelets).

In the following descriptions, amounts are exemplary, and may be varied.U937 cytoplasmic extracts may be prepared by sonicating U937 cells(ATCC: Catalogue No. CRL-159) in lysis buffer (M-PER mammalian proteinextraction reagent, Pierce catalog #78501 containing 10% ProteaseInhibitor Cocktail For Use with Mammalian Cell and Tissue Extracts,Sigma catalog #P8340). Sonicated cell extracts are then centrifuged at70,000 g for 30 minutes and supernatants removed. Sucrose is added to afinal concentration of 0.25 M, then the extracts are aliquoted andstored at −80° C.

PDE reactions are performed using the Phosphodiesterase [³H] cAMP SPAenzyme assay as described by the manufacturer (Amersham PharmaciaBiotech; http://www.apbiotech.com; catalog # 7090). Briefly, the assayis run for 60 minutes at room temperature in 50 μL volumes in 1 μM [³H]cAMP, 50 mM Tris Cl, 10 mM MgCl₂ pH 7.5. U937 extract is added such thatless than 10% of substrate was consumed. Test compound or vehicle isadded to the desired concentration. Typically, compounds are tested atsix 10-fold dilutions ranging from 100 μM to 1 nM. Reactions areperformed in duplicate. Reactions are terminated with 50 μl of YttriumSPA beads and then counted on a Packard Scintillation counter(TopCount™) for 1 minute.

Utilizing the PDE assay conditions described above with PDE4, typicalPDE4 inhibitors such as ROLIPRAM™ and Ro-20-1724 (Calbiochem: CatalogueNo. 557502) give IC₅₀ values in agreement with those found in theliterature (reviewed in Schudt et al., 1996).

Inhibition of PDE4 (or more accurately, specific isoforms of PDE4) withsubsequent elevation of intracellular cAMP and protein kinase Aactivation is a therapeutic target in inflammatory or autoimmunediseases where the causal cells or tissues involved predominantlyexpress this PDE isoform. With respect to rheumatoid arthritis, the PDE4inhibitor ROLIPRAM™ has been shown to be active in animal models of thedisease such as collagen-induced arthritis in the rat (Nyman et al.,Clin. Exp. Immunol. 108(3), 415-419, 1997).

Compounds including a benzyl group according to the process of thepresent invention typically demonstrate PDE4 inhibition with reducedemetogenic potential, relative to the corresponding non benzylatedanalog. The efficacy of a compound as a PDE4 inhibitor with diminishedemetogenic potential may be measured by determining the extent to whichthe compound displaces ROLIPRAM™ from its preferred binding site (knownas the High Affinity Binding Site, or HARBs) on PDE4. Animal models haveshown that a compound's antiinflammatory efficacy as a PDE4 inhibitor ishighly correlated with its potency at inhibiting PDE4 catalytic activityrather than its ability to displace [³H]-ROLIPRAM™ from a high affinitybinding site from cells within the brain and central nervous system(Duplantier 1996, Barnette 1996). Compounds having benzyl groupsaccording to the present invention displayed a low affinity for theHARBS conformer of PDE4 suggesting that these compounds are not likelyto be plagued by mechanism-associated side-effects associated with firstgeneration PDE4 inhibitors such as ROLIPRAM™.

In order to perform this assay, female CD1 mice are sacrificed via theintraperitoneal injection of 100 μL ethanol, and the brain tissue ishomogenized in 5 mL of ice-cold Tris-HCl, pH 8.00 supplemented with 1.2mM MgCl₂, 1 mM benzamidine (Sigma; Catalogue No. B 6506) and 0.1 mM PMSF(Sigma; Catalogue No. P 7626). The suspension is centrifuged twice at30,000×G at 4° C. and then the supernatant discarded. The pellet isresuspended in buffer, and adjusted to a protein concentration of 0.5mg/mL. Compounds to be tested are dissolved in DMSO and pipetted intriplicate into a 96 well microplate at concentrations ranging from 1 to30,000 nM. 10 mL of membrane preparation is supplemented with 100 μL of0.235 μM [³H]-ROLIPRAM™ in DMSO, and 100 μL is dispensed into each wellof the microplate. The plate is incubated at 4° C. for 1 hour. Contentsof the plate are aspirated through a Whatman GF/C filterplate, andrinsed with 4×200 μL ice-cold buffer. The plate is dried overnight, andthen 30 μL of Microscint 20 (Packard; Catalogue No. 6013621) is added toeach well, and plate is read in the scintillation counter with asampling time of 2 minutes/well. Values representing non-specificbinding (defined by counts obtained using 20 μM ROLIPRAM™) aresubtracted from all data points. Triplicate determinations should beperformed at each concentration. The PDE4:HARBS value indicates theratio of the IC₅₀ concentration required to inhibit catalytic activityto the concentration required to displace 50% of ROLIPRAM™ from the highaffinity binding site.

Under these assay conditions ROLIPRAM™ is able to displace ³H- ROLIPRAM™from a high-affinity binding site in mouse brain with an IC₅₀ of about 6nM (data not shown). Thus, ROLIPRAM™ binds with 65 fold greater affinityto its high affinity site than the concentration required forhalf-maximal inhibition of PDE4 catalytic activity. This preferentialaffinity for HARBS over the catalytic conformer has been correlated withthe negative side effects of first generation PDE4 inhibitors; namelyemesis and CNS effects.

Benzylated compounds according to the present invention are less potentat binding to this HARBS site than ROLIPRAM™. For example, see theLPDE4:HPDE4 ratio reported for compound 25 in Table 1 in the Examplebelow. Thus, compounds of the present invention may display in-vivoemetogenic effects that are much less than ROLIPRAM™, Ro 20-1724 orother first generation PDE4 inhibitors.

Utility of Compounds and Compositions of the Present Invention

The compounds disclosed herein, or compositions comprising one of moreof these compounds and a pharmaceutically acceptable carrier, diluent orexcipient, may be used in a method for various treatments andprophylactic effects. For instance, the compounds of the invention maybe used for treating or preventing an inflammatory condition or diseasein a patient, where the method comprises administering to the patient inneed thereof an amount of a compound or composition according to thepresent invention, where the amount is effective to treat or prevent theinflammatory condition or disease of the patient. The compounds andcompositions of the present invention are particularly advantageous inthat they provide the desired activity, e.g. treatment of inflammation,without attendant undesirable emetogenic side-effects.

The inflammatory condition or disease may be an autoimmune condition ordisease; the inflammatory condition or disease may involve acute orchronic inflammation of bone and/or cartilage compartments of joints;the inflammatory condition or disease may be an arthritis selected fromrheumatoid arthritis, gouty arthritis or juvenile rheumatoid arthritis;the inflammatory condition or disease may be asthma; the condition ordisease may be associated with the disregulation of T-cells; thecondition or disease may be associated with elevated levels ofinflammatory cytokines (e.g., wherein the inflammatory cytokine is IL-2,IL-4, IL-5, or Il-12, or wherein the inflammatory cytokine is IFN-γ, orwherein the inflammatory cytokine is TNF-α); the inflammatory conditionor disease may be multiple sclerosis; the inflammatory condition ordisease may be pulmonary sarcadosis.; the inflammatory condition ordisease may be ocular inflammation or allergy; the inflammatorycondition or disease may be an inflammatory bowel disease (e.g., Crohn'sdisease or ulcerative colitis); and the inflammatory condition ordisease may be an inflammatory cutaneous disease (e.g., psoriasis ordermatitis).

Furthermore, the present invention provides a method for modulatingintracellular cyclic adenosine 3′,5′-monophosphate levels within apatient, comprising administering to a patient in need thereof an amountof a compound or composition according to the present invention, whereinthe amount is effective to modulate the intracellular cyclic adenosine3′,5′-monophosphate levels of the patient. The patient may have aninflammatory condition or disease.

Furthermore, the present invention provides a method for treating orpreventing a disease or condition in a patient, where the disease orcondition is associated with pathological conditions that are modulatedby inhibiting enzymes associated with secondary cellular messengers, themethod comprising administering to a patient in need thereof an amountof a compound or a composition of the present invention, wherein theamount is effective to treat or prevent a disease or conditionassociated with pathological conditions that are modulated by inhibitingenzymes associated with secondary cellular messengers. The enzyme may bea cyclic AMP phosphodiesterase; or the enzyme may be a phosphodiesterase4.

Furthermore, the present invention provides a method of treating orpreventing transplant rejection in a patient, comprising administeringto a patient in need thereof an amount of a compound or composition ofthe present invention, where the amount is effective to treat or preventtransplant rejection in the patient. The rejection may be due to graftversus host disease.

Furthermore, the present invention provides a method of treating orpreventing uncontrolled cellular proliferation in a patient, comprisingadministering to a patient in need thereof an amount of a compound orcomposition according to the present invention, where the amount iseffective to treat or prevent uncontrolled cellular proliferation in thepatient. The uncontrolled cellular proliferation may be caused by acancer selected from leukemia and solid tumors.

Furthermore, the present invention provides a method of treating orpreventing conditions associated with the central nervous system (CNS)in a patient, comprising administering to a patient in need thereof anamount of a compound or composition according to the present invention,where the amount is effective to treat or prevent conditions associatedwith the central nervous system (CNS) in the patient. The conditionassociated with the central nervous system (CNS) may be depression.

In one aspect the present invention provides a method for treating orpreventing an inflammatory condition or disease in a patient. The methodincludes administering to the patient in need thereof an amount of abenzylated PDE4 inhibitor or composition containing a benzylated PDE4inhibitor as described in the various inventive aspects and embodimentsdescribed herein, where the amount is effective to treat or prevent theinflammatory condition or disease of the patient. Optionally, thebenzylated PDE4 inhibitor inhibits an enzyme selected fromphosphodiesterase 4 A, B, C or D or any combination thereof includingall splice variants of PDE4 A, B, C and D. In one aspect, theinflammatory condition or disease is an autoimmune condition or disease.In another aspect, the inflammatory condition or disease involves acuteor chronic inflammation of bone and/or cartilage compartments of joints.In another aspect, the inflammatory condition or disease is an arthritisselected from rheumatoid arthritis, gouty arthritis or juvenilerheumatoid arthritis. In another aspect, the inflammatory condition ordisease is asthma. In another aspect, the inflammatory condition ordisease is associated with the disregulation of T-cells. In anotheraspect, the inflammatory condition or disease is associated withelevated levels of inflammatory cytokines. Optionally, the inflammatorycytokine is IL-2, IL-4, IL-5, or IL-12. Optionally, the inflammatorycytokine is IFN-γ. Optionally, the inflammatory cytokine is TNF-α. Inanother aspect, the inflammatory condition or disease is multiplesclerosis. In another aspect, the inflammatory condition or disease ispulmonary sarcadosis. In another aspect, the inflammatory condition ordisease is ocular inflammation or allergy. In another aspect, theinflammatory condition or disease is an inflammatory bowel disease.Optionally, the inflammatory bowel disease is Crohn's disease orulcerative colitis. In another aspect, the inflammatory condition ordisease is an inflammatory cutaneous disease. Optionally, theinflammatory cutaneous disease is psoriasis or dermatitis. In anotheraspect, the inflammatory condition or disease is chronic obstructivepulmonary disease (COPD), bronchitis, emphysema or acute respiratorydistress syndrome (ARDS).

In another aspect the present invention provides a method for treatingor preventing a disease or condition in a patient, where the disease orcondition is associated with pathological conditions that are modulatedby inhibiting enzymes associated with secondary cellular messengers. Theinventive method includes administering to the patient in need thereofan amount of a benzylated PDE4 inhibitor or composition containing abenzylated PDE4 inhibitor as described in the various inventive aspectsand embodiments described herein, wherein the amount is effective totreat or prevent a disease or condition associated with pathologicalconditions that are modulated by inhibiting enzymes associated withsecondary cellular messengers. In one aspect, the enzyme is a cyclic AMPphosphodiesterase. In another aspect, the enzyme is phosphodiesterase 4.

In another aspect the present invention provides a method for treatingor preventing transplant rejection in a patient. The inventive methodincludes administering to the patient in need thereof an amount of abenzylated PDE4 inhibitor or composition containing a benzylated PDE4inhibitor as described in the various inventive aspects and embodimentsdescribed herein, where the amount is effective to treat or preventtransplant rejection in the patient. In one aspect, the rejection is dueto graft versus host disease.

In another aspect the present invention provides a method for treatingor preventing uncontrolled cellular proliferation in a patient. Themethod includes administering to the patient in need thereof an amountof a benzylated PDE4 inhibitor or composition containing a benzylatedPDE4 inhibitor as described in the various inventive aspects andembodiments described herein, where the amount is effective to treat orprevent uncontrolled cellular proliferation in the patient. In oneaspect, the uncontrolled cellular proliferation is caused by a cancerselected from leukemia and solid tumors.

In another aspect, the present invention provides a method of treatingor preventing conditions associated with the central nervous system(CNS) in a patient. The method includes administering to the patient inneed thereof an amount of a benzylated PDE4 inhibitor or compositioncontaining a benzylated PDE4 inhibitor as described in the variousinventive aspects and embodiments described herein, where the amount iseffective to treat or prevent conditions associated with the centralnervous system (CNS) in the patient. In one aspect, the conditionassociated with the CNS is depression. In another aspect, the conditionassociated with the CNS is long-term memory potentiation and learningenhancement.

In another aspect, the present invention provides a method of treatingor preventing diseases in a patient, where the disease is associatedwith viral infection. The method includes administering to the patientin need thereof an amount of a benzylated PDE4 inhibitor or compositioncontaining a benzylated PDE4 inhibitor as described in the variousinventive aspects and embodiments described herein, where the amount iseffective to treat or prevent diseases associated with viral infectionin the patient. In one aspect, the viral infection is due to the humanimmunodeficiency virus (HIV) and the disease is acquiredimmunodeficiency syndrome (AIDS).

In another aspect, the present invention provides a method of treatingor preventing diseases in a patient, where the disease is associatedwith infection by a parasite. The method includes administering to thepatient in need thereof an amount of a benzylated PDE4 inhibitor orcomposition containing a benzylated PDE4 inhibitor as described in thevarious inventive aspects and embodiments described herein, where theamount is effective to treat or prevent diseases associated withinfection of the patient by a parasite. In one aspect, the parasiticinfection is due to the trypanosoma brucei and the disease is Africansleeping sickness disease.

In another aspect, the present invention provides a method of treatingor preventing cystic fibrosis in a patient. The method includesadministering to the patient in need thereof an amount of a benzylatedPDE4 inhibitor or composition containing a benzylated PDE4 inhibitor asdescribed in the various inventive aspects and embodiments describedherein, where the amount is effective to treat or prevent cysticfibrosis in the patient.

In a method of the present invention, a benzylated compound, or acomposition comprising one or more benzylated and a pharmaceuticallyacceptable carrier, diluent or excipient, may, although need not,achieve one or more of the following desired results in the subject towhom has been administered a benzylated compound as defined above, or acomposition containing one of these compounds and a pharmaceuticallyacceptable carrier, diluent or excipient:

-   -   1. Inhibition of cyclic-AMP phosphodiesterase 4;    -   2. Low ratio of IC₅₀ PDE4(cat):IC₅₀PDE4(HARBS);    -   3. Inhibition of TNF-α production;    -   4. Inhibition of edema;    -   5. Inhibition of reactive oxygen species generation from primary        neutrophils;    -   6. Oxygen radical scavenging;    -   7. Potentiate induction of CRE-mediated transcription activity        in human monocytic cells;    -   8. Inhibition of PDE, preferably PDE4, PDE3, or PDE3 and PDE4;    -   9. Inhibition of cytokine production by activated T-cell        subsets;    -   10. Inhibition of neutrophil myeloperoxidase release;    -   11. Inhibition of neutrophil chemotaxis;    -   12. Inhibition of graft rejection;    -   13. Inhibition of clinical and histopathological parameters of        disease in inflammatory bowel disease;    -   14. Inhibition of clinical and histopathological parameters of        arthritis in a murine collage-induced arthritis model; and    -   15. Inhibition of clinical and histopathological parameters of        disease in an allergan-induced guinea-pig model of acute        bronchoconstriction.

Thus, the inventive method may be used to treat inflammation, includingboth acute and chronic inflammation as well as certain proliferativedisorders (cancers). As used herein, inflammation includes, withoutlimitation, ankylosing spondylitis, arthritis (where this termencompasses over 100 kinds of rheumatic diseases), asthma, Crohn'sdisease, fibromyalgia syndrome, gout, inflammations of the brain(including multiple sclerosis, AIDS dementia, Lyme encephalopathy,herpes encephalitis, Creutzfeld-Jakob disease, and cerebraltoxoplasmosis), emphysema, inflammatory bowel disease, irritable bowelsyndrome, ischemia-reperfusion injury, juvenile erythematosus, pulmonarysarcoidosis, Kawasaki disease, osteoarthritis, pelvic inflammatorydisease, psoriatic arthritis (psoriasis), rheumatoid arthritis,psoriasis, tissue/organ transplant, scleroderna, spondyloarthropathies,systemic lupus erythematosus, pulmonary sarcoidosis, and ulcerativecolitis. As used herein, proliferative disorders includes, withoutlimitation, all leukemias and solid tumors that are susceptible toundergoing differentiation or apoptosis upon interruption of their cellcycle.

A method of the present invention is the administration of atherapeutically effective amount of a benzylated compound as describedherein including salts, compositions etc. thereof. As used herein, theactual amount encompassed by the term “therapeutically effective amount”will depend on the route of administration, the type of warm-bloodedanimal being treated, and the physical characteristics of the specificwarm-blooded animal under consideration. These factors and theirrelationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors that those skilled in the medical arts will recognize.

An effective amount of a compound or composition of the presentinvention will be sufficient to treat inflammation in a warm-bloodedanimal, such as a human. Methods of administering effective amounts ofanti-inflammatory agents are well known in the art and include theadministration of inhalation, oral or parenteral forms. Such dosageforms include, but are not limited to, parenteral solutions, tablets,capsules, sustained release implants and transdermal delivery systems;or inhalation dosage systems employing dry powder inhalers orpressurized multi-dose inhalation devices.

The dosage amount and frequency are selected to create an effectivelevel of the agent without harmful effects. It will generally range froma dosage of about 0.001 to 100 mg/Kg/day, and typically from about 0.01to 10 mg/Kg/day where administered orally or intravenously. Also, thedosage range will be typically from about 0.001 to 1 mg/Kg/day whereadministered intranasally or by inhalation.

The following examples are offered by way of illustration and not by wayof limitation.

Unless otherwise stated, flash chromatography and column chromatographymay be accomplished using Merck silica gel 60 (230-400 mesh). Flashchromatography may be carried out according to the procedure set forthin: “Purification of Laboratory Chemicals”, 3rd. edition,Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D. Perrin and W. L.F. Armarego, page 23. Column chromatography refers to the processwhereby the flow rate of eluent through a packing material is determinedby gravity. In all cases flash chromatography and radial chromatographymay be used interchangeably. Radial chromatography is performed usingsilica gel on a Chromatotron Model #7924T (Harrison Research, Palo Alto,Calif.). Unless otherwise stated, quoted R_(f) values are obtained bythin layer chromatography using Silica Gel 60 F₂₅₄ (Merck KGaA, 64271,Darmstadt, Germany).

Also, unless otherwise stated, chemical reactants and reagents wereobtained from standard chemical supply houses, such as Aldrich(Milwaukee, Wis.; www.aldrich.sial.com); EM Industries, Inc. (Hawthorne,N.Y.; www.emscience.com); Fisher Scientific Co. (Hampton, N.H.;www.fischer1.com); and Lancaster Synthesis, Inc. (Windham, N.H.;www.lancaster.co.uk). Gases were obtained from Praxair (Vancouver,B.C.). Cell lines, unless otherwise stated, where obtained from publicor commercial sources, e.g., American Tissue Culture Collection (ATCC,Rockville, Md.).

EXAMPLES Example 1 Formation of Benzylation Agent from CorrespondingBenzyl Alcohol

Synthesis of Compound 2

To a rapidly stirred slurry of 3-methoxy-4-hydroxybenzyl alcohol 1 (30.0g, 195 mmol), potassium carbonate (62.2 g, 450 mmol), and 18-crown-6(0.40 g, 1 mol %) in toluene (350 mL) was added a solution of benzylbromide (BnBr, 25.6 g, 150 mmol) in toluene (150 mL) over 20 min. Thereaction mixture was refluxed for 16 hours, after which the mixture wasdiluted with diethyl ether (400 mL) and washed successively with NaOH (1N, 2×250 mL), saturated aqueous NaHCO₃ (2×250 mL), and brine (2×300 mL).The diethyl ether layer was dried over anhydrous MgSO₄, and the solventwas removed to provide a pale yellow solid (42.1 g) which wascrystallized with EtOAc and hexanes to give compound 2 (32.7 g, 77%) asa white crystalline solid.

Synthesis of Compound 3

To a solution of alcohol 2 (3.20 g, 13.1 mmol) in anhydrous diethylether (15 mL) was added PBr₃ (1.77 g, 6.55 mmol) in one portion, and theresulting mixture was stirred at room temperature for 3 hours. Themixture was diluted with diethyl ether (40 mL) and washed with H₂O (2×30mL), saturated NaHCO₃ (2×30 mL), and brine (2×30 mL). The ether layerwas dried over anhydrous MgSO₄, and the solvent was removed underreduced pressure to afford compound 3 (4.02 g, 100%) as a light yellowsolid.

Example 2 Formation of Benzylation Agent from Corresponding BenzylAldehyde

Scheme 3 illustrates several procedures for converting commerciallyavailable benzyl aldehydes into the corresponding benzyl alcohol.Suitable solvents may be employed in any of these reactions.

Synthesis of Compound 14

To a suspension of 4-hydroxy-3-nitrobenzaldehyde 13 (3.00 g, 17.95mmol), potassium carbonate (3.73 g, 26.93 mmol) in DMF (300 mL) wasslowly added benzyl bromide (2.85 mL, 23.96 mmol). The reaction mixturewas stirred at 65° C. for 18 hours. After cooling to room temperature,the mixture was diluted with water (140 mL) and extracted with diethylether (3×150 mL). The combined organic layers were washed with water(150 mL) and brine (150 mL). After drying over anhydrous MgSO₄,filtration and evaporation of the filtrate in vacuo gave crude compound14 (4.39 g, 95%) which was used for the next reaction without furtherpurification.

Synthesis of Compound 15

Compound 14 (4.30 g, 16.72 mmol) was dissolved in EtOH/CH₂Cl₂ (1:1, 50mL) and cooled to 0° C. NaBH₄ (0.63 g, 16.72 mmol) was addedportionwise. After the addition was completed, the ice-water bath wasremoved and the reaction mixture was stirred at room temperature for 2hours. Water (40 mL) was added and the mixture was extracted with CH₂Cl₂(3×60 mL). The combined organic layers were washed with brine (50 mL)and dried over anhydrous MgSO₄. Removal of the solvent gave a paleyellow solid which was purified by silica gel column chromatography(hexanes/EtOAc, 1:1) to give compound 15 (4.31 g, 99%) as a pale yellowsolid.

Synthesis of Compound 16

To a solution of compound 15 (4.30 g, 16.59 mmol) in anhydrous diethylether (40 mL) was slowly added PBr₃ (0.79 mL, 8.30 mmol) via syringe,and the resulting mixture was stirred at room temperature for 3 hours.The mixture was diluted with EtOAc (100 mL) and washed with saturatedaqueous NaHCO₃ (2×50 mL) and brine (2×50 mL). The organic layer wasdried over anhydrous MgSO₄, and the solvent was removed under reducedpressure to afford compound 16 (5.07 g, 95%) as a pale yellow solid.

Example 3 Formation of Benzylated PDE4 Inhibitor from Benzylation Agentand Corresponding Non-Benzylated Inhibitor

A. Benzylation using various halide compounds to provide the desiredbenzylated products may be achieved as shown in Scheme 4. In Scheme 4,compound 17 is benzylated with commercially available 3,4-difluorobenzylbromide to give the desired compound 18 in 59% yield.

Synthesis of Compound 18

n-Butyllithium (2.5 M solution in hexanes, 0.56 mL, 1.40 mmol) was addedto a solution of diisopropylamine (0.20 mL) in dry THF (10 mL) at −78°C. The mixture was stirred at −78° C. for 1 hour, then HMPA. (0.33 mL,1.91 mmol) was added, followed by addition of a solution of compound 17(0.30 g, 1.27 mmol) in THF (3 mL). After 1 hour, a solution of3,4-difluoro benzyl bromide (purchased from Aldrich Chemical Company,Inc., 0.32 mL, 2.54 mmol)) was added in one portion to the reaction, andthe resulting mixture was stirred at −78° C. for an additional 4 hours.The excess base was quenched with saturated aqueous NH₄Cl (10 mL), andthe resulting solution was extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with saturated NaCl (2×30 mL), dried overMgSO₄, filtered and the filtrate evaporated to dryness. The residue waspurified by column chromatography on silica gel (hexanes/EtOAc, 2:1) togive compound 18 (0.27 g, 59%) as a white solid.

B. In Scheme 5, compound 17 is benzylated with 3,4-dibenzyloxy benzylbromide (prepared by treatment the corresponding alcohol with PBr₃),followed by hydrogenation using 10% Pd/C as catalyst to give the desiredcompound 21 in good yield.

Synthesis of Compound 19

To a solution of 3,4-dibenzyloxybenzyl alcohol (1.35 g, 4.21 mmol) inanhydrous diethyl ether (25 mL) was added PBr₃ (0.20 mL, 2.11 mmol) inone portion, and the resulting mixture was stirred at room temperaturefor 3 hours. The mixture was diluted with diethyl ether (50 mL) andwashed with H₂O (2×30 mL), saturated NaHCO₃ (2×30 mL), and brine (2×30mL). The ether layer was dried over anhydrous MgSO₄, and the solvent wasremoved under reduced pressure to afford compound 19 (1.47 g, 91%) as alight yellow oil.

Synthesis of Compound 20

n-Butyllithium (2.5 M solution in hexanes, 0.38 mL, 0.931 mmol) wasadded to a solution of diisopropylamine (0.14 mL 0.999 mmol) in dry THF(3 mL) at −78° C. The mixture was stirred at −78° C. for 1 hour, thenHMPA (0.22 mL, 1.27 mmol) was added, followed by adding a solution ofcompound 17 (200.0 mg, 0.846 mmol) in THF (3 mL). After 1 hour, asolution of 3,4-dibenzyloxy benzyl bromide (compound 19, 248.5 mg, 0.80mmol) in THF (1 mL) was added in one portion to the reaction, and theresulting mixture was stirred at −78° C. for an additional 4 hours. Theexcess base was quenched with saturated aqueous NH₄Cl (10 mL), and theresulting solution was extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with saturated NaCl (2×30 mL), dried overMgSO₄, filtered and the filtrate evaporated to dryness. The residue waspurified by column chromatography on silica gel (hexanes/EtOAc, 2:1) togive compound 20 (0.31 g, 67%) as a colorless oil.

Synthesis of Compound 21

A mixture of compound 20 (0.20 g, 0.37 mmol) and 10% Pd/C (25 mg) inEtOAc/AcOH (4:1, 5 mL) was stirred under H₂ (balloon) for 2 hours. Themixture was then filtered through a celite plug and the filtrate wasevaporated to dryness. The residue was purified by column chromatographyon silica gel (hexanes/EtOAc, 3:2) to give compound 21 (0.093 mg, 70%)as a colorless syrup.

Example 4 Formation of Alpha-Benzylated ROLIPRAM™

Further exemplary synthetic methodology to provide a benzylatedROLIPRAM™ compound is described below. For example, as illustrated inScheme 6, N-protection of 22 (prepared according to the literatureprocedure: Journal of Medicinal Chemistry, 1993, 36, 3274-3277) withdi-tert-butyl dicarbonate and triethylamine in dichloromethane providesN-t-butoxycarbonylamide derivative 23. Alkylation of compound 23with4-(benzyloxy)-3-methoxybenzyl bromide 3 affords compound 24. Any numberof alkylations can be carried out using different halides and theappropriate base such as LDA. Removal of the N-BOC protecting group inwith trifluoroacetic acid in dichloromethane gives compound 25.Hydrogenolysis of compound 25 using 10% Pd/C as catalyst provides thedesired product 26.

Preparation of Compound 23

Di-tert-butyl dicarbonate (0.793 mg, 3.63 mmoles) was added to asolution of compound 22 (0.50 g, 1.82 mmoles), Et₃N (0.50 mL, 3.63mmoles) and DMAP (0.044 g) in CH₂Cl₂ (14 mL). The mixture was stirred atroom temperature for 4 hours. The mixture was concentrated, and theresidue was purified by column chromatography on silica gel eluted withhexane/EtOAc (3:2) to afford compound 23 (0.655 g, 96%) as light yellowwax.

Preparation of Compound 24

To a solution of compound 23 (0.649 g, 1.73 mmoles) in dry THF (13 mL)under argon was slowly added LDA [1.20 mmoles, prepared from n-BuLi(0.83 mL, 2.5 M solution in hexane, 1.20 mmoles) and diisopropylamine(0.30 mL, 2.16 mmoles)] in THF (3 mL) at −78° C. The mixture was stirredat −78° C. for one hour, and then DMPU (0.60 mL, 1.50 mmoles) was addedto the above mixture via syringe. After 15 minutes,4-(benzyloxy)-3-methoxybenzyl bromide 3 (1.06 g, 3.46 mmoles) in THF(1.5 mL) was added. The resulting mixture was stirred for an additional4 hours at −78° C. The excess base was quenched at 0° C. with aqueoussaturated NH₄Cl (20 mL), and the resulting solution was extracted withEtOAc (3×30 mL). The combined organic layer was washed with saturatedbrine (2×30 mL), dried over MgSO₄, filtered and the filtrate wasevaporated to dryness. The residue was purified by column chromatographyon silica gel eluted with hexanes/EtOAc (7:3) to give compound 24 (0.829g, 80%) as a white foam.

Preparation of Compound 25

Trifluoroacetic acid (14 mL) was added to a solution of compound 24(0.820 g, 1.36 mmoles) in CH₂Cl₂ (14 mL). The mixture was stirred atroom temperature for 2 hours, diluted with CH₂Cl₂ (100 mL) and washedwith saturated NaHCO₃ solution (3×20 mL). The organic layer was driedover MgSO₄, filtered and the filtrate was evaporated to dryness. Theresidue was purified by column chromatography over silica gel usingethyl acetate as eluent to afford compound 25 (0.510 g, 75%) as whitesolid.

Preparation of Compound 26

A mixture of compound 25 (0.356 g, 0.710 mmoles) and 10% Pd/C (36 mg) inEtOAc/AcOH (1:1, 12 mL) was stirred under H₂ (balloon pressure) for 18hours. The mixture was filtered on celite and the filtrate wasevaporated to dryness. The residue was purified by column chromatographyon silica gel eluted with Hexanes/EtOAc (10:90) to afford compound 26(0.20 g, 84%) as a white foam.

Example 5 Formation of N-Benzylated ROLIPRAM™

An example of N-benzylation using benzyl halide to provide the desiredproduct 27 is illustrated in Scheme 7. In scheme 7, compound 22 isbenzylated with 4-(cyclopentyloxy)-3-methoxybenzyl bromide 44 to providedesire compound 27.

Example 6 Formation of Beta-Benzylated ARIFLO™ (33)

As illustrated in Scheme 8, compound 28 (prepared according to theliterature procedure: Journal of Medicinal Chemistry, 1998, 41, 821-835)is alkylated with 4-(benzyloxy)-3-methoxybenzyl bromide 3 to providecompound 29, which is saponified and decarboxylated to cyclohexanone 30with sodium chloride in hot aqueous DMSO. Cyclohexanone 30 ishomologated by a Peterson-type reaction with excess2-lithio-2-(trimethylsilyl)-1,3-dithiane (prepared from2-TMF-1,3-dithiane and n-butyl lithium in THF) to provide ketenedithioacetal 31. Methanolysis of compound 31 with mercuric chloride andperchloric acid provides ester 32. Saponification of the ester 32 withpotassium hydroxide in a THF/methanol/water solvent mixture, followed byacidification with aqueous HCl, is used to provide the desired product33.

Example 7 Formation of Gamma-Benzylated ARIFLO™ (39)

Exemplary synthetic methodology to introduce a benzyl or substitutedbenzyl group at the carbon γ to the carbonyl group of a compound offormula (28) is described below. For example, as illustrated in Scheme9, compound 28 (prepared according to the literature procedure: Journalof Medicinal Chemistry, 1998, 41, 821-835) may be saponified anddecarboxylated to compound 34 with sodium chloride in hot aqueous DMSO.The cyclohexenone ring may be generated using isopropenyl acetate andp-toluenesulphonic acid (TsOH) followed by Pd(OAc)₂, Bu₃Sn(OMe) andCH₂CHOCO₂CH₃. Addition of a benzyl group at the beta position of thecyclohexenone ring may be achieved by a Michael-type addition usingcommercially available benzylmagnesium chloride as shown in Scheme 9 toyield compound 36. Any number of substituted organomagnesium ororganolithium benzyl groups may be prepared and used in Michael-typereactions according to the methods described in Comprehensive OrganicTransformations, A Guide to Functional Group Preparations, SecondEdition, Richard C. Larock, John Wiley and Sons, Inc., 1999, orreferenced therein. Cyclohexanone 36 is homologated by a Peterson-typereaction with excess 2-lithio-2-(trimethylsilyl)-1,3-dithiane to provideketene dithioacetal 37. Methanolysis of compound 37 with mercuricchloride and perchloric acid provides ester 38. Hydrolysis of the ester38 with potassium hydroxide in a THF/methanol/water solvent mixture,followed by acidification with aqueous HCl, may provide the desiredproduct 39.

Example 8 Formation of Alpha-Benzylated ARIFLO™ (41)

Treatment of compound 40 (prepared according to the literatureprocedure: Journal of Medicinal Chemistry, 1998, 41, 821-835) with LDAin THF at −78° C., followed by 4-(benzyloxy)-3-methoxybenzyl bromide 44may provide the desired compound 41. In Scheme 10, Ocyclopentylrepresents cyclopentyloxy.

Preparation of Compound 41

To a cooled solution of diisopropylamine in anhydrous THF at −78° C. wasadded n-butyllithium under argon. The mixture was then stirred at −78°C. for 1 hour. To this was added a solution of compound 40 in a mixtureof anhydrous THF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.The reaction mixture was stirred at −78° C. for 1 hour and then4-(cyclopentyloxy)-3-methoxybenzyl bromide (Compound 44, preparedaccording to Scheme 11 below) in anhydrous THF was added in one portion.The resulting mixture was stirred at −78° C. for an additional 3 hours,warmed to 0° C., and diluted with 2 N HCl. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed with 2 NHCl, followed by brine, and then dried over MgSO₄. The mixture wasfiltered, and the filtrate was evaporated to dryness. The resultingresidue was purified by silica gel column chromatography to affordcompound 41.

In Scheme 11, treatment of compound 42 with cyclopentyl bromide,potassium iodide and potassium carbonate in DMF gives the correspondingO-cyclopentyl (OcPent) derivative 43, which is treated with PBr₃ indiethyl ether to give desired bromide compound 44.

Synthesis of Compound 43

To a suspension of 4-hydroxy-3-methoxybenzyl alcohol 42 (1.00 g, 6.49mmol), potassium carbonate (1.79 g, 12.98 mmol) and potassium iodide(29.1 mg, 0.175 mmol) in DMF (10 mL) was slowly added cyclopentylbromide (0.91 mL, 8.44 mmol). The reaction mixture was stirred at 65° C.for 24 hours. After cooling to room temperature, the mixture was dilutedwith diethyl ether (50 mL) and washed with water (2×25 mL). Drying overanhydrous MgSO₄, filtration and evaporation of the filtrate in vacuogave crude yellow solid which was purified by silica gel columnchromatography (hexanes/EtOAc, 3:1) to give compound 43 (0.502 g, 35%)as a pale yellow solid.

Synthesis of Compound 44

To a solution of compound 43 (0.48 g, 2.17 mmol) in anhydrous diethylether (8 mL) was slowly added PBr₃ (0.10 mL, 1.09 mmol) via syringe, andthe resulting mixture was stirred at room temperature for 2 hours. Themixture was diluted with diethyl ether (50 mL) and washed with saturatedaqueous NaHCO₃ (2×25 mL) and brine (2×25 mL). The organic layer wasdried over anhydrous MgSO₄, and the solvent was removed under reducedpressure to afford compound 44 (0.577 g, 93%) as a white solid.

Example 9 Formation of N-Benzylated WAY-PDA-641

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 45 is described in Scheme 12. In Scheme 12, compound 45(i.e., WAY-PDA-641) is treated with NaH in DMF, followed by3,4-difluorobenzyl bromide to give the desired compound 46 (i.e.,benzylated WAY-PDA-641).

Example 10 Formation of N-Benzylated Ro-20-1724

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 47 is described in Scheme 13. In Scheme 13, compound 47(i.e., Ro-20-1724) is treated with NaH in DMF, followed by3,4-difluorobenzyl bromide to give the desired compounds 48 and 49(i.e., benzylated Ro-20-1724 compounds). Excess NaH and3,4-difluorobenzyl bromide may be used to provide the compound withbenzyl groups on both nitrogens.

Example 11 Formation of N-Benzylated RP 73401

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 50 is described in Scheme 14. In Scheme 14, compound 50(i.e., RP 73401) is treated with NaH in DMF, followed by3,4-difluorobenzyl bromide to give the desired compound 51 (i.e.,benzylated RP 73401).

Example 12 Formation of N-Benzylated CP-80,633-A

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 52 is described in Scheme 15. In Scheme 15, compound 52(i.e., CP-80,633-A) is treated with NaH in DMF, followed by3,4-difluorobenzyl bromide to give the desired compound 53 (i.e.,benzylated CP-80,633-A). Excess NaH and 3,4-difluorobenzyl bromide maybe used to provide the compound with benzyl groups on both nitrogens.

Example 13 Formation of N-Benzylated AROFYLLINE™

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 54 is described in Scheme 16. In Scheme 16, compound 54(AROFYLLINE™) is treated with NaH in DMF, followed by 3,4-difluorobenzylbromide to give the desired compound 55 (i.e., benzylated AROFYLLINE™).

Example 14 Formation of N-Benzylated CIPAMFYLLINE™

Exemplary synthetic methodology to introduce a substituted benzyl groupinto compound 56 is described in Scheme 17. In Scheme 17, compound 56(i.e., CIPAMFYLLINE™) is treated with KOtBu in DMF, followed by3,4-difluorobenzyl bromide to give the desired compound 57 (i.e.,benzylated CIPAMFYLLINE™).

Example 15 In Vitro Testing for Emetogenic Response

Table 1 shows the PDE4 and HARBS activities of compounds of the presentinvention compared to that of ROLIPRAM™. Compounds 25 and 26 (see Scheme6) comprise two different derivatives of ROLIPRAM™ in which thesubstitution pattern of the added benzyl group at the alpha positiondiffers. As these data clearly show, benzylation at the alpha carbonposition of ROLIPRAM™ dramatically reduces the HARBS binding affinity ofthese derivatives by 92 and 56 fold for compound 26 and 25,respectively. In reducing the HARBS binding affinities the PDE4:HARBSratios for these compounds is also dramatically reduced to 1.1 and 2.5for compounds 25 and 26 respectively compared to 65 for ROLIPRAM™. Thiseffect on the HARBS affinities and the ratio of PDE4:HARBS is expectedto result in reduced emetogenic potential as well as improvedtherapeutic window for these compounds.

TABLE 1 EFFECT OF BENZYLATION AT THE ALPHA POSITION OF ROLIPRAM ™ ONPOTENCY OF PDE4 INHIBITION AND BINDING TO THE HARBS SITE OF PDE4. α-PDE4 substitution IC₅₀ HARBS IC₅₀ Ratio Compound (+/− benzyl) (μM) (μM)(PDE4/HARBS) ROLIPRAM ™ No 0.42 .0065 65.1 26 Yes 1.49 .6012 2.5 25 Yes0.40 .3608 1.1

These data also show that the nature of the alpha-positioned benzylsubstituent influences the degree of reduction in HARBS binding as wellas the reduction in potency of PDE4 inhibitory activity. The example ofcompound 25 also shows that the HARBS binding affinity of ROLIPRAM™ maybe reduced without affecting the PDE4 inhibitory activity (andanti-inflammatory efficacy) by the correct choice of benzyl substituent.

Table 2 shows the PDE4 and HARBS activities of a compound of the presentinvention compared to that of ARIFLO™. Compound 41 is a derivative ofARIFLO™ in which a substituted benzyl group has been added to the carbonalpha to the carboxyl group. The data show that benzylation at the alphaposition of ARIFLO™ reduces the HARBS binding affinity of thisderivative by 7.9 fold relative to that of the parent compound. In thisexample the potency in inhibition of PDE4 catalytic activity is alsoreduced 7.5 fold for the benzylated derivative resulting in animprovement in the PDE4/HARBS ratio from 2.4 to 2.2.

TABLE 2 EFFECT OF BENZYLATION AT THE ALPHA POSITION OF ARIFLO ™ ONPOTENCY OF PDE4 INHIBITION AND BINDING TO THE HARBS SITE OF PDE4. PDE4α-substitution IC₅₀ HARBS IC₅₀ Ratio Compound (+/− benzyl) (μM) (μM)(PDE4/HARBS) ARIFLO ™ No 0.18 .076 2.4 41 Yes 1.35 .6012 2.2

As demonstrated by the above examples for benzylation of ROLIPRAM™, thenature of the added benzyl group (substitution pattern) may stronglyinfluence the degree of improvement of the PDE4:HARBS ratio andtherefore a different benzyl group added to the alpha carbon of ARIFLO™could confer improved ratios relative to the example above.

Additionally, the site of addition of the benzyl group to the PDE4inhibitor may strongly influence the degree of improvement (reduction)in the PDE 4:HARBS ratio relative to the non-benzylated compound. Assuch, addition of a benzyl moiety to the beta or gamma carbons ofARIFLO™ may be desirable to that of alpha substitution as in the aboveexample.

Example 16 In Vivo Testing for Emetogenic Response

The most recognized pre-clinical animal model for emesis is the ferret.The ferret undergoes a very characteristic, reproducible andwell-documented series of behavioral responses, including backwardwalking, pawing of the mouth, arching of the back, retching and vomitingwhen dosed with an emetogenic compound. With respect to PDE4 inhibitorstheir emetogenic potential has been correlated with the ability ofcompounds to bind to a conformer of the enzyme to which ROLIPRAM™ bindswith nanomolar affinity (the HARBS binding site). The central nervoussystem (CNS) and emetic effects of PDE4 inhibitors are therefore thoughtin large part to be due to the interaction of these compounds with thisparticular conformer of PDE4 which is especially prevalent in both thecentral and peripheral nervous system as well as in cells of the lumenof the gastrointestinal tract (i.e., parietal cells of the stomach).

Benzylation of compounds with PDE4 inhibitory activity (PDE4 inhibitors)according to the present invention has been shown to reduce their HARBSbinding potency (see EXAMPLE 15) and thus by logical and rationaleextension, based on the existing body of knowledge in the field, toreduce their emetogenic potential. To confirm the in-vitro data of thepresent invention indicating that incorporation of a benzyl group at thealpha position of ROLIPRAM™ reduces binding to the HARBS conformer ofPDE4 compared to that of the parent compound ROLIPRAM™, these twocompounds were evaluated for emetogenic potency after intravenousinfusion in the ferret model of emesis.

Protocol

Adult male ferrets (Mustela putorius furo, sable, 0.75-1.5 kg, MarshallFarms, USA) were quarantined and acclimated to the testing facility forseven days prior to initiation of the study. For intravenous infusiondosing, a catheter was surgically inserted in the jugular vein a minimumof 14 hours prior to administration of test articles and the catheterwas maintained for patency by flushing with heparin solution daily.After surgery for catheter insertion the ferrets were individuallyhoused in cages. Animals were fasted 12-16 hours prior to dosing andduring the behavioral assessment period. They were returned to normalfood diet after the observation periods. Animals found acceptable forinclusion in the study were randomly assigned to the each of the studygroups (n=3 for each of the two treatment groups and n=3 for the vehiclenegative control group).

Test compounds (ROLIPRAM™ and Compound 25) were freshly dissolved on theday of dosing in the vehicle, polyethylene glycol (PEG) 200 (Sigmacatalogue number P-3015), to the required concentration in order toachieve the target dose. Animals in the control (PEG 200) and treatment(ROLIPRAM™ or Compound 25) groups were administered the dosingformulation at 3 ml/kg by intravenous infusion over a 5 minute periodvia the catheter inserted in the jugular. Continual observation forsigns of emetic behavior were begun for each of the animals in the studygroups immediately following completion of the 5 minute dosing periodand for a period of three hours. Sequential recordings of emeticbehaviour were noted on a separate data collection sheet for each animalwhich included the time of onset of each event as well as the durationand nature of the event (i.e., retching, gagging, vomiting, backarching, backward walking etc.).

The target doses for each of the test articles are shown below in Table3. If animals expressed no emetic behaviour at the lowest dosage thenanimals were dosed again with semi-log increasing doses of test articleand the three hour observation period repeated until the emeticthreshold (lowest of test doses causing emesis) was reached or until thehighest of the 4 target doses was completed. There was a 24 hr. washoutperiod between each of the successive ascending doses of test article toallow the compound to clear the animals' system. For a dose level to beconsidered at the threshold of emesis at least one of the ferrets musthave exhibited definite emetic signs (i.e., retching and/or vomiting).If the emetic response was minimal at a particular dose level then thenext dose level could be performed to confirm the threshold level.

TABLE 3 STUDY GROUP DESIGNATIONS FOR DETERMINATION OF EMETIC THRESHOLDIN FERRETS OF ROLIPRAM ™ AND BENZYLATED ROLIPRAM ™ Treatment No. ofanimals Route Dosage (mg/kg) Vehicle (PEG 200) 3 i.v. — ROLIPRAM ™ 3i.v. 0.03, 0.1, 0.3, 1.0 Compound 25 3 i.v. 0.1, 0.3, 1.0, 3.0Results

Table 4 shows the dosage required for each of the test compounds(rolipram and compound 25) to achieve a threshold emetic response after5 minutes intravenous infusion in the ferret. A threshold emeticresponse was achieved after dosing with 0.3 mg/kg rolipram. At thisdosage level of rolipram, one of the three ferrets exhibited a definiteemetic response as shown by 5 mild retches observed over a time periodof 9 minutes starting at 10 minutes post-dosing. Emetic signs were alsoevident for rolipram at the previous 0.1 mg/kg dose level.

In contrast to rolipram there was no emetic behaviour whatsoeverdemonstrated by the ferrets administered compound 25 up to and includingthe highest dose level tested (3 mg/kg). Thus for compound 25 the emeticthreshold in ferrets is greater than 3 mg/kg after intravenous infusiondosing. These data therefore show that at least 10-fold higher doses ofthe benzylated compound are required to achieve emesis compared to thenon-benzylated compound, rolipram. Since these compounds have equivalentPDE4 catalytic inhibitory activity, the benzylated compound in additionto being significantly less emetic than its non-benzylated parent, wouldbe expected to have similar anti-inflammatory efficacy and thus amarkedly improved therapeutic ratio.

These in-vivo data demonstrated in the ferret model of emesis, thereforeconfirm and support the in-vitro biochemical findings presented abovethat benzylation reduces binding of compounds to the HARBS conformer ofPDE4 and thus reduces their emetogenic potential.

TABLE 4 COMPARISON OF THE EMETIC THRESHOLD OF ROLIPRAM AND BENZYLATEDROLIPRAM AFTER INTRAVENOUS INFUSION IN FERRETS Treatment EmeticThreshold (mg/kg) Rolipram 0.3 Compound 25 >3.0

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually incorporated by reference. For example, the book inComprehensive Organic Transformations, A Guide to Functional GroupPreparations, Second Edition, Richard C. Larock, John Wiley and Sons,Inc., 1999, and particularly the references cited therein, isincorporated herein by reference for all purposes.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A method for preparing a benzylated PDE4 inhibitor having reducedemetogenic potential relative to the non-benzylated PDE4 inhibitor,wherein the benzylated PDE4 inhibitor has the following formula:

wherein Bzl has the formula:

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen, and wherein themethod comprises reacting a PDE4 inhibitor having the following formula:

where the protecting group is a suitable protecting group for a nitrogenatom; with a benzylating agent having the following formula:

wherein n, each R¹ and each numeral 1, 2, 3, 4 and 5 are as definedabove for the benzylated PDE4 inhibitor and the leaving group is ahalogen or a sulfonate, under basic conditions to form the benzylatedPDE4 inhibitor as defined above.
 2. A method for preparing a benzylatedPDE4 inhibitor having reduced emetogenic potential relative to thenon-benzylated PDE4 inhibitor, wherein the benzylated PDE4 inhibitor hasthe following formula:

wherein Bzl has the formula:

wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen,with the proviso that the ring is aromatic and contains at least 3carbon atoms; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen, and wherein themethod comprises reacting a PDE4 inhibitor having the following formula:

with a benzylating agent having the following formula:

wherein n, each R¹ and each numeral 1, 2, 3, 4 and 5 are as definedabove for the benzylated PDE4 inhibitor and the leaving group is ahalogen or a sulfonate, under basic conditions to form the benzylatedPDE4 inhibitor as defined above.
 3. The method of claim 1 wherein theprotecting group is BOC.
 4. The method of claim 1 wherein the leavinggroup is chloride, bromide, mesylate or tosylate.
 5. The method of claim1 wherein the basic conditions are created by first combining the PDE4inhibitor with a base in a suitable solvent, followed by reaction with abenzylating agent.
 6. The method of claim 5 wherein the base is sodiumhydride, potassium hydride, lithium diisopropylamide, lithium hydroxide,sodium hydroxide, potassium hydroxide, sodium alkoxy or potassiumalkoxide.
 7. The method of claim 1 wherein each of the numerals 1, 2, 3,4 and 5 may be carbon or nitrogen, with the proviso that the ring isaromatic and contains at least 4 carbon atoms; n is 5 and R¹ at eachoccurrence is independently selected from halogen, nitro, R², and OR²wherein R² at each occurrence is independently selected from H,C₁-C₈alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in thealkyl portion, C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl,hydroxyalkyl, carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl,amide, alkylamide, phenyl, phenylalkyl having 1-8 carbons in the alkylportion, phenylaminoalkyl having 2-6 carbons in the alkyl portion andthe amino may be optionally substituted with C₁-C₄alkyl and indanyl;wherein the alkyl portion of an R² group may be optionally substitutedwith one or more fluorine atoms, hydroxyl or C₁-C₈alkoxy; and the phenylportion of an R² group may be optionally substituted with C₁-C₈alkyl,C₁-C₈alkoxy or halogen.
 8. The method of claim 1 wherein each of thenumerals 1, 2, 3, 4 and 5 is carbon, with the proviso that the ring isaromatic; n is 5 and R¹ at each occurrence is independently selectedfrom halogen, nitro, R², NR² _((m)), and OR² wherein m=0, 1, 2, or 3 andR² at each occurrence is independently selected from H, C₁-C₈alkyl,alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons inthe alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion,C₃-C₇cycloalkyl, C₆-C₉polycycloalkyl, alkylcycloalkyl, hydroxyalkyl,carboxylate, alkylcarboxylate, carboxyl, alkyl carboxyl, amide,alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkylhaving 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6carbons in the alkyl portion and the amino may be optionally substitutedwith C₁-C₄alkyl and indanyl; wherein the alkyl portion of an R² groupmay be optionally substituted with one or more fluorine atoms, hydroxylor C₁-C₈alkoxy; and the aryl portion of an R² group may be optionallysubstituted with C₁-C₈alkyl, C₁-C₈alkoxy or halogen.